ZIB

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Electronic Resource

Clinical pharmacokinetics of Neoral in pediatric recipients of primary liver transplants (1997)

Wallemacq, P. E. ; Reding, Raymond ; Sokal, Etienne M. ; [et al.]

Springer

Transplant international 10 (1997), S. 466-470

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ISSN: 1432-2277

Keywords: Key words Pediatric liver transplantation ; Neoral ; pharmacokinetics ; Liver transplantation ; pediatric ; Neoral ; Neoral ; liver transplantation ; pediatric ; Pharmacokinetics ; Neoral ; pediatric liver transplantation

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Pediatric liver transplant recipients constitute a population characterized by a particularly unpredictable and poor bioavailability of cyclosporin (CyA). Even though several adult studies show that the new oral formulation of CyA, Neoral (NEO), produces better bioavailability and blood level predictability, few data describe its pharmacokinetics in children. We performed a complete analysis of the pharmacokinetics of NEO in ten small children after primary liver transplantation. Three pharmacokinetic profiles were set up with data obtained from tests taken during i. v. administration of CyA, after the first oral NEO dose, and after the last NEO dose before discharge from the hospital. The mean half-lives obtained were 8.1, 7.7, and 6.9 h, respectively, and the bioavailabilities were 22 % and 21 % for the first and last NEO doses. A large interpatient variability was observed. This was due, in part, to episodes of diarrhea that interfered with the pharmacokinetic evaluation and, in part, to the variability of post-transplant hepatic function. There was a good correlation between CyA trough levels and their related AUCs for both NEO profiles (r = 0.93 and r = 0.74, respectively). We conclude that, even though the pediatric OLT population remains more unpredictable than that of adults, NEO has a relatively rapid half-life and a remarkably improved bioavailability.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s001470050088

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Cardiovascular effects of different infusion rates of sufentanil in patients undergoing coronary surgery (1997)

Borenstein, M. ; Shupak, R. ; Barnette, R. ; [et al.]

Springer

European journal of clinical pharmacology 51 (1997), S. 359-366

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ISSN: 1432-1041

Keywords: Key words Sufentanil ; pharmacokinetics ; haemo dynamics ; different infusion rates ; coronary surgery

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Objective: Pharmacokinetics and haemodynamic effects of a total dose of 15 μg · kg−1 sufentanil, an opioid anaesthetic agent, were studied in patients undergoing aortocoronary bypass surgery at three infusion rates of 30 (group I), 5 (group II), and 2 (group III) μg · kg−1 · min−1, respectively. Results: Plasma concentrations of sufentanil could be optimally characterized by a linear biexponential pharmacokinetic model. Non-compartmental analyses indicated that there was no significant difference in the values of clearance (11.6, 13.3, 14.3 ml · min−1 · kg−1), steady-state volume of distribution (0.220, 0.255 and 0.331 l · kg−1) and mean residence time (18.8, 13.3 and 14.3 min) among the groups. The observed mean Cmax values of 421 (group I), 125 (group II), and 53 (group III) ng · ml−1 and observed mean AUC values from 0 to 3 min were all consistent with the dosing regimens. There were large inter-individual variations in haemodynamic response. Compared to plasma data, a delay in haemodynamic effects was found. Times to reach peak haemodynamic effect ranged from 4.3 to 4.9 min for group I, from 4.6 to 6.1 min for group II, and from 9.9 to 11.3 for group III. Except heart rate, peak haemodynamic effects in these study patients generally ranged from 20.9% to 35.2%. Significant reductions in the area under the effect-time profiles of mean arterial blood pressure and systemic vascular resistance were observed in group II and group III, but not in group I. Significant reductions in the area under the effect-time profiles of left ventricular stroke work index were observed in group III only. No effect on heart rate was found in any group. Conclusion: Our findings suggested that a slower infusion rate of sufentanil at a dose of 15 μg · kg−1 tends to give a greater reduction in mean arterial blood pressure, systemic vascular resistance, and left ventricular stroke work index than does a faster infusion rate.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002280050214

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Population analysis of the non-linear red blood cell partitioning of draflazine following various infusion durations (1997)

Snoeck, E. ; Piotrovskij, V. ; Jacqmin, P. ; [et al.]

Springer

European journal of clinical pharmacology 53 (1997), S. 57-63

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ISSN: 1432-1041

Keywords: Key wordsDraflazine ; Population analysis; nucleoside transport inhibitor ; non-linear red blood cell partition ing ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Objective: The pharmacokinetics and non-linear red blood cell partitioning of the nucleoside transport inhibitor draflazine were investigated in 19 healthy male and female subjects (age range 22–55 years) after a 15-min i.v. infusion of 1 mg, immediately followed by infusions of variable rates (0.25, 0.5 and 1 mg · h−1) and variable duration (2–24 h). Methods: The parameters describing the capacity-limited specific binding of draflazine to the nucleoside transporters located on erythrocytes were determined by NONMEM analysis. The red blood cell nucleoside transporter occupancy of draflazine (RBC occupancy) was evaluated as a pharmacodynamic endpoint. Results: The population typical value for the dissociation constant K d (%CV) was 0.648 (12) ng · ml−1 plasma, expressing the very high affinity of draflazine for the erythrocytes. The typical value of the specific maximal binding capacity Bmax (%CV) was 155 (2) ng · ml−1 RBC. The interindividual variability (%CV) was moderate for K d (38.9%) and low for Bmax (7.8%). As a consequence, the variability in RBC occupancy of draflazine was relatively low, allowing the justification of only one infusion scheme for all subjects. The specific binding of draflazine to the red blood cells was a source of non-linearity in draflazine pharmacokinetics. Steady-state plasma concentrations of draflazine virtually increased dose-proportionally and steady state was reached at about 18 h after the start of the continuous infusion. The t1/2βaveraged 11.0–30.5 h and the mean CL from the plasma was 327 to 465 ml · min−1. The disposition of draflazine in whole blood was different from that in plasma. The mean t1/2β was 30.2 to 42.2 h and the blood CL averaged 17.4–35.6 ml · min−1. Conclusion: Although the pharmacokinetics of draflazine were non-linear, the data of the present study demonstrate that draflazine might be administered as a continuous infusion over a longer time period (e.g., 24 h). During a 15-min i.v. infusion of 1 mg, followed by an infusion of 1 mg · h−1, the RBC occupancy of draflazine was 96% or more. As the favored RBC occupancy should be almost complete, this dose regimen could be justified in patients.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002280050337

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Effects of grapefruit juice ingestion – pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men (1997)

Lundahl, J. ; Regårdh, C. G. ; Edgar, B. ; [et al.]

Springer

European journal of clinical pharmacology 52 (1997), S. 139-145

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ISSN: 1432-1041

Keywords: Key words Felodipine ; Dietary interaction ; Flavonoids; pharmacodynamics ; pharmacokinetics ; grapefruit juice

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Objective: To examine the effect of grapefruit juice on the metabolism of felodipine following intravenous and oral administration. Methods: The study had a randomised, four-way, crossover design in 12 healthy males. Single doses of felodipine were given as an intravenous infusion for 1 h (1.5 mg) or as an oral extended release (ER) tablet (10 mg). Grapefruit juice (150 ml) or water was ingested 15 min prior to drug intake. Results: Intake of grapefruit juice did not significantly alter the intravenous pharmacokinetics of felodipine compared to control treatment, whereas after oral drug administration it did lead to an increase in the mean AUC and Cmax by 72% and 173%, respectively, and the mean absolute bioavailability was increased by 112%. The fraction of the oral felodipine dose reaching the portal system was increased from 45% to 80% when intake of drug was preceded by grapefruit juice ingestion. The pharmacokinetics of the primary metabolite, dehydrofelodipine, was affected by the intake of juice, resulting in a 46% increase in Cmax. Juice intake immediately before oral felodipine resulted in more pronounced haemodynamic effects of the drug as measured by diastolic blood pressure and heart rate. However, the haemodynamic effects of the intravenous administration were not altered by juice intake. Vascular-related adverse events were reported more frequently when oral drug administration was preceded by juice intake compared with control treatment. Taking grapefruit juice immediately prior to intravenous felodipine administration did not cause any alteration in the adverse event pattern. Conclusion: The main acute effect of the grapefruit juice on the plasma concentrations of felodipine is mediated by inhibition of gut wall metabolism.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002280050263

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5

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Pharmacokinetics and pharmacodynamics of ranitidine in renal impairment (1997)

Koch, K. M. ; Liu, M. ; Davis, I. M. ; [et al.]

Springer

European journal of clinical pharmacology 52 (1997), S. 229-234

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ISSN: 1432-1041

Keywords: Key words Ranitidine ; Renal impairment; dose adjustment ; pharmacodynamics ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Objective: The pharmacodynamics and pharmacokinetics of ranitidine were examined in subjects with varying degrees of renal function to determine the effect of this condition on acid-antisecretory activity. Methods: Subjects with creatinine clearances (CCr) ranging from 0 to 213 ml · min−1 received single 50-mg and 25-mg i.v. doses of ranitidine. This was followed by determination of serum and urine ranitidine concentrations, and continuous gastric pH monitoring for 24 h. Results: Serum ranitidine concentrations were described by a two-compartment model linked to a sigmoidal Emax model describing gastric pH. Ranitidine renal clearance, ranging from 0 to 1003 ml · min−1, correlated with CPAH (r 2 = 0.707), while non-renal clearance was unaltered. Steady-state volume of distribution decreased by half in severe renal impairment. No changes in the effective concentration at half-maximal response (EC50), maximal response (Emax), or basal response (E0) were observed. Thus, renal elimination of ranitidine declined in parallel with renal function, while sensitivity to the pharmacologic effect (gastric pH elevation) was unaltered. Ranitidine was well tolerated in these renally impaired subjects. Conclusion: These data indicate that the current recommendation for renal impairment dose reduction (by two-thirds when CCr〈50 ml · min−1) might result in under-treating moderately impaired patients, and suggests a less conservative dose reduction (by half when CCr〈10 ml · min−1) to avoid therapeutic failure while remaining within the wide margin of safety for this drug.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002280050279

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Pharmacokinetic interaction study of citalopram and cimetidine in healthy subjects (1997)

Priskorn, M. ; Larsen, F. ; Segonzac, A. ; [et al.]

Springer

European journal of clinical pharmacology 52 (1997), S. 241-242

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ISSN: 1432-1041

Keywords: Key words Citalopram ; Cimetidine; drug ; drug interac‐tion ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002280050282

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Pharmacokinetics and bioavailability of oral and intramuscular artemether (1997)

Karbwang, J. ; Na-Bangchang, K. ; Congpuong, K. ; [et al.]

Springer

European journal of clinical pharmacology 52 (1997), S. 307-310

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ISSN: 1432-1041

Keywords: Key words Artemether ; Thai males; malaria ; dihydroartemisinin ; pharmacokinetics ; bioavailability

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Objective: The pharmacokinetics and bioavailability of artemether and dihydroartemisinin were investigated in eight Thai males following the administration of single oral and intramuscular doses of artemether (300 mg) in a randomized two-way cross-over study. Results: Both oral and intramuscular artemether were well-tolerated. In most cases, artemether and dihydroartemisinin were detected in plasma after 30 min and declined to levels below the limit of detection within 18–24 h. Compared with intramuscular administration, oral administration of artemether resulted in a relatively rapid but incomplete absorption [Cmax: 474 vs 540 ng · ml−1; t max: 2.0 vs 3.9 h; AUC: 2.17 vs 5.20 μg · h · ml−1]. Geographic means of lag-time and absorption half-life (t 1/2a) of oral vs intramuscular artemether were 0.28 and 1.1 h vs 0.30 and 2 h, respectively. t 1/2z was significantly shortened after the oral dose [2.8 vs 6.9 h]. Mean oral bioavailability relative to intramuscular administration was 43.2%. The ratio of the AUCs of artemether to dihydroartemisinin was significantly lower after the oral than after the intramuscular dose (geometric mean: 0.29 vs 0.60).

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002280050295

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Itraconazole moderately increases serum concentrations of oxybutynin but does not affect those of the active metabolite (1997)

Lukkari, E. ; Juhakoski, A. ; Aranko, K. ; [et al.]

Springer

European journal of clinical pharmacology 52 (1997), S. 403-406

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ISSN: 1432-1041

Keywords: Key words Oxybutynin ; Itraconazole; N-desethyloxy‐butynin; drug interaction ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Objective: Oxybutynin has low oral bioavailability due to an extensive presystemic metabolism. It has been suggested that the biotransformation of oxybutynin is dependent on CYP3A. Because itraconazole, a widely used mycotic, is a potent inhibitor of CYP3A4, we wanted to study a possible interaction between oxybutynin and itraconazole. Methods: In this double-blind, randomized, two-phase cross-over study, ten healthy volunteers received either 200 mg itraconazole or placebo for 4 days. On day 4, each volunteer ingested a single dose of 5 mg oxybutynin. Serum concentrations of oxybutynin, its active metabolite N-desethyloxybutynin, and itraconazole were monitored over 24 h. Results: Itraconazole significantly increased both the area under the serum drug concentration-time curve (AUC0–t) and the peak concentration of oxybutynin twofold. The AUC0–t and the peak concentration of N-desethyloxybutynin were not significantly affected by itraconazole. Itraconazole did not change the peak time or the elimination half-life of either oxybutynin or N-desethyloxybutynin. The occurrence of adverse events after oxybutynin administration was not increased by itraconazole. Conclusions: Itraconazole moderately increases serum concentrations of oxybutynin, probably by inhibiting the CYP3A-mediated metabolism. However, the concentrations of N-desethyloxybutynin were practically unchanged. Since about 90% of the antimuscarinic activity of oxybutynin is attributable to N-desethyloxybutynin, any interaction of oxybutynin with CYP3A4 inhibiting drugs has only minor clinical significance.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002280050309

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Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam (1997)

Ahonen, J. ; Olkkola, K. T. ; Neuvonen, P. J.

Springer

European journal of clinical pharmacology 51 (1997), S. 415-419

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ISSN: 1432-1041

Keywords: Key words Midazolam ; Fluconazole ; CYP3A4 ; interaction ; pharmacokinetics ; pharmacodynamics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Objective: Midazolam is a short-acting benzodiazepine hypnotic extensively metabolized by CYP3A4 enzyme. Orally ingested azole antimycotics, including fluconazole, interfere with the metabolism of oral midazolam during its absorption and elimination phases. We compared the effect of oral and intravenous fluconazole on the pharmacokinetics and pharmacodynamics of orally ingested midazolam. Methods: A double-dummy, randomized, cross-over study in three phases was performed in 9 healthy volunteers. The subjects were given orally fluconazole 400 mg and intravenously saline within 60 min; orally placebo and intravenously fluconazole 400 mg; and orally placebo and intravenously saline. An oral dose of 7.5 mg midazolam was ingested 60 min after oral intake of fluconazole/placebo, i.e. at the end of the corresponding infusion. Plasma concentrations of midazolam, α-hydroxymidazolam and fluconazole were determined and pharmacodynamic effects were measured up to 17 h. Results: Both oral and intravenous fluconazole significantly increased the area under the midazolam plasma concentration-time curve (AUC0–3, AUC0–17) 2- to 3-fold, the elimination half-life of midazolam 2.5-fold and its peak concentration (Cmax) 2- to 2.5-fold compared with placebo. The AUC0–3 and the Cmax of midazolam were significantly higher after oral than after intravenous administration of fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effects of midazolam but no differences were detected between the fluconazole phases. Conclusion: We conclude that the metabolism of orally␣administered midazolam was more strongly inhibited by oral than by intravenous administration of fluconazole.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002280050223

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Pharmacokinetic-pharmacodynamic modelling as a tool to evaluate the clinical relevance of a drug-food interaction for a nisoldipine controlled-release dosage form (1997)

Schaefer, H. G. ; Heinig, R. ; Ahr, G. ; [et al.]

Springer

European journal of clinical pharmacology 51 (1997), S. 473-480

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ISSN: 1432-1041

Keywords: Key words Nisoldipine ; Hypertension; Ca antagonist ; pharmacokinetics ; pharmacodynamics ; PK/PD modelling

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Objective: Nisoldipine, a calcium antagonist of the dihydropyridine class, has been used in the treatment of hypertension and angina pectoris. A new controlled-release dosage form (nisoldipine coat-core, NCC) has been developed to allow once daily dosing. In addition to a formal food interaction study as requested by regulatory authorities for controlled-release dosage forms, a subsequent study was conducted to determine the clinical relevance of the changes in nisoldipine plasma concentration vs time profiles seen in the food effect study. Methods: After a placebo run-in phase of 6 days, 12 hypertensive patients started treatment with 20 mg NCC once daily (days 0–3, 5–6, 8–9). On days 4, 7 and 10 the NCC was substituted for 5, 10 and 20 mg nisoldipine solution, respectively, in order to obtain nisoldipine plasma concentration vs time profiles comparable to the ones resulting from the concomitant intake of food and NCC. Simultaneous measurements of blood pressure (BP) and nisoldipine concentration were performed on days 3, 4, 7 and 10. Results: The relationship between nisoldipine plasma concentrations and percentage reduction in BP [diastolic (DBP) and systolic (SBP), supine and standing] could be described by an Emax model. The mean maximum reduction (Emax) relative to baseline was about 36.4% and 37.7% (DBP, supine and standing) and 27.9% and 29.2% (SBP, supine and standing), respectively. The interindividual variability (% CV) in Emax was low, ranging from 17.6% to 28.8%. The mean nisoldipine plasma concentration corresponding to 50% of the maximum effect (EC50) ranged between 0.99 and 2.62 μg · l–1 with a pronounced interindividual variability (% CV) of 89.5–108.8%. Mean Cmax values after administration of the 30 and 40 mg NCC together with food were 4.5 and 7.5 μg · l–1, respectively. Based on the concentration-effect relationship established in the present study, the effect achieved with a concentration of 7.5 μg · l–1 will be about 77% of Emax for DBP and about 88% of Emax for SBP, respectively. Conclusion: At the time of maximum plasma concentration the additional decrease in BP relative to baseline due to the food effect will be about 7–15% for DBP and 3–9% for SBP. After administration of the 10␣mg solution with a mean Cmax of 8.7 μg · l–1, only headache and flush with mild severity have been reported as adverse events. These maximum concentrations are comparable to Cmax values seen after intake of 40 mg NCC with food. With regard to heart rate (HR) there were distinct differences between the two formulations: Following administration of 5, 10 and 20 mg nisoldipine solution, there were dose-dependent increases in HR by a maximum of 4, 12 and 16 beats · min−1, respectively, whereas the HR profile for the NCC was similar to that seen under placebo treatment.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002280050233

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Influence of an acidic beverage (Coca-Cola) on the absorption of itraconazole (1997)

Jaruratanasirikul, S. ; Kleepkaew, A.

Springer

European journal of clinical pharmacology 52 (1997), S. 235-237

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ISSN: 1432-1041

Keywords: Key words Itraconazole ; Coca Cola; acidic beverage ; absorption ; pharmacokinetics ; drug concentration ; food

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Objective: To evaluate the effectiveness of Coca-Cola in enhancing the absorption of itraconazole. Methods: Eight healthy volunteers were randomized to receive two treatment sequences in a two-way crossover design with a 1-week wash-out period separating each study treatment. Treatment I, the control, consisted of 100 mg itraconazole with 325 ml water. Treatment II was identical to treatment I, except that itraconazole was administered with 325 ml of Coca-Cola (pH 2.5). Results: Serum itraconazole concentrations, after administration with Coca-Cola (treatment II), were higher than after administration with water (treatment I). The mean AUC was 1.12 vs 2.02 μg · h · ml−1, the mean Cmax was 0.14 vs 0.31 μg · ml −1and the mean tmax was 2.56 vs 3.38 h in treatments I and II, respectively. Conclusion: The absorption of itraconazole can be enhanced by Coca-Cola.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002280050280

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Single-dose pharmacokinetics of paracetamol and its conjugates in Chinese non-insulin-dependent diabetic patients with renal impairment (1997)

Chan, M. T. V. ; Anderson, P. J. ; Chan, J. C. N. ; [et al.]

Springer

European journal of clinical pharmacology 52 (1997), S. 285-288

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ISSN: 1432-1041

Keywords: Key words Paracetamol ; Renal failure; polar conjugates ; non-insulin-dependent diabetes mellitus (NIDDM) ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Objective: A single oral dose of paracetamol (20 mg · kg−1) was given to 38 Chinese patients with non-insulin-dependent diabetes mellitus (NIDDM) who had either normal renal function or varying degrees of renal impairment, with creatinine clearances ranging from 4 to 123 ml · min−1 · 1.73 m−2. The plasma and urinary concentrations of paracetamol and its major metabolites were measured by high-performance liquid chromatography (HPLC). Results: The absorption and elimination of paracetamol were unaffected by renal impairment. However, the area under the plasma concentration time curve and the elimination half-life of paracetamol metabolites increased significantly with worsening renal insufficiency. Mean renal clearances of paracetamol and its conjugates were significantly reduced in these subjects. There was no evidence of altered metabolic activation with renal impairment. Conclusion: The results demonstrate that paracetamol disposition is minimally affected by diabetic nephropathy; however, extensive accumulation of conjugates may occur.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002280050291

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Pharmacokinetics and pharmacodynamic effects of the angiotensin II antagonist valsartan at steady state in healthy, normotensive subjects (1997)

Müller, P. ; Flesch, G. ; de Gasparo, M. ; [et al.]

Springer

European journal of clinical pharmacology 52 (1997), S. 441-449

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ISSN: 1432-1041

Keywords: Key words Angiotensin II ; Valsartan; AT1 receptor antagonist ; healthy volunteers ; pharmacokinetics ; renin-angiotensin system ; blood pressure ; passive tilting

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Objective: Pharmacokinetics, pharmacodynamic effects and tolerability of 200 mg valsartan, once-daily for 8 days, were investigated in 16 healthy, normotensive volunteers on a normal sodium diet. Methods: This was a double-blind, placebo-controlled, randomized crossover study. Drug concentrations in plasma and urine, angiotensin II (Ang II) concentrations in plasma, systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR) in the supine position and 3 min after passive head-up tilting, as well as safety parameters (ECG, clinical chemistry and hematology, renal water and electrolyte excretion) were measured over 24 h after the first dose (day 1) and at steady state on day 8. Results: Absorption and distribution of valsartan were rapid (Cmax, 2 h; t½λ1 〈 1 h), followed by a slower terminal elimination phase (t½λ2, 6 h) on days 1 and 8, with little accumulation in plasma (increase of 20% on day 8). Less than 10% of the dose was excreted unchanged in urine. The increase in plasma Ang II (Cmax, 6 h) was significantly enhanced at steady state. Supine SBP and DBP significantly decreased on day 8 only, by an average of −3.6 and −2.4 mmHg, respectively, versus placebo, without a concomitant increase in HR. Upon passive tilting, the increase in DBP, normally reinforced by sympathetic renin release, was slightly but significantly blunted on day 1 (−2.0 mmHg) and day 8 (−4.0 mmHg) of treatment with valsartan versus placebo. The orthostatic reflex increase in HR was slightly enhanced compared with placebo by an average of 2.8 beats · min−1 on day 1 and by 2.9 beats · min−1 on day 8. Valsartan was well tolerated and had no influence on ECG, clinical laboratory parameters, and water, electrolyte and uric acid excretion. Conclusions: Pharmacokinetics of valsartan are unchanged after multiple once-daily dosing, with little (expected) accumulation in plasma. Effects of 200 mg valsartan on blood pressure in healthy subjects on a normal sodium intake are small and become more prominent after repeated dosing. Indirect evidence of AT1 blockade by valsartan is demonstrated by an increase of plasma Ang II and by a blunted DBP response to passive tilting. The decrease in blood pressure at steady state enhances the increase in plasma Ang II. Valsartan is well tolerated and is devoid of effects on water, electrolyte and uric acid excretion at 200 mg per day in healthy normotensive volunteers.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002280050317

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Genetic polymorphism of CYP2C19 and lansoprazole pharmacokinetics in Japanese subjects (1997)

Katsuki, H. ; Nakamura, C. ; Arimori, K. ; [et al.]

Springer

European journal of clinical pharmacology 52 (1997), S. 391-396

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ISSN: 1432-1041

Keywords: Key words Lansoprazole ; CYP2C19; genotype ; hydroxy lation ; polymorphism ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Objective: We investigated whether interindividual differences in the pharmacokinetic disposition of lansoprazole are attributed to the genetic polymorphism of CYP2C19 which occurred by two mutations, CYP2C19m1 and CYP2C19m2, in 20 Japanese subjects. Methods: Polymerase chain reaction (PCR) restriction fragment length polymorphism procedures were used to detect the CYP2C19m1 mutation in exon 5 and the CYP2C19m2 mutation in exon 4 using SmaI and BamHI, respectively. Results: Ten subjects were homozygous (wt/wt subjects) for the wt allele in both exon 5 and exon 4, four subjects were heterozygous (wt/m1) for the CYP2C19m1 mutation, and two subjects were heterozygous (wt/m2) for the CYP2C19m2. The remaining four subjects had both mutated alleles in CYP2C19 genes, i.e., two were homozygous (m1/m1) for the defect in exon 5 and two were heterozygous (m1/m2) for the two defects in exons 5 and 4. The subjects in group 1 (wt/wt, wt/m1 and wt/m2) were the extensive metabolizers (EMs) for 5-hydroxylation of lansoprazole and were in the range of hydroxylation indexes from 3.83 to 19.8, whereas the subjects in group 2 (m1/m1 and m1/m2) were the poor metabolizers (PMs) and the indexes were in the range of 38.5 to 47.6. In group 2, AUC, t1/2 and CL/f of lansoprazole were significantly greater, longer, and lower, respectively, than those in group 1. Conclusion: The hydroxylation of lansoprazole to 5-hydroxylansoprazole was apparently impaired in the subjects with the genetic defects of CYP2C19 (m1/m1 or m1/m2).

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002280050307

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Pharmacokinetics of nicardipine enantiomers in healthy young volunteers (1997)

Inotsume, N. ; Iwaoka, T. ; Honda, M. ; [et al.]

Springer

European journal of clinical pharmacology 52 (1997), S. 289-292

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ISSN: 1432-1041

Keywords: Key words Nicardipine; enantiomers ; healthy volunteers ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Objectives: The present study was conducted to compare pharmacokinetic behaviors of nicardipine enantiomers given in different doses with different formulations of racemic nicardipine in healthy volunteers. Methods: One or two 20-mg racemic nicardipine tablets, and a 40-mg sustained-release capsule of nicardipine were administered to eight healthy volunteers in a cross-over fashion and pharmacokinetic parameters were evaluated. Enantiomer concentrations were determined by GC-MS combined with chiral stationary phase HPLC. Results and conclusions: Serum concentration of (+)-nicardipine was approximately 2–3 times higher than that of (−)-nicardipine in 20- and 40-mg doses of conventional formulations and a non-linear increase in bioavailability with dose was demonstrated. The value for AUC of (+)-nicardipine was approximately 2.3–2.8 times greater than that of the (−)-nicardipine (P 〈 0.05) when 20 and 40 mg racemic nicardipine were administered in a conventional preparation. Relative bioavailability of the sustained-release preparation vs the conventional preparation was 28% and 44% for (+)- and (−)-nicardipine, respectively, for the 40-mg dose.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002280050292

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Transdermal nitroglycerin: clinical and pharmacokinetic consequences of renewing the patch and the application site (1997)

Klemsdal, T. O. ; Mundal, H. H. ; Bredesen, J. E. ; [et al.]

Springer

European journal of clinical pharmacology 52 (1997), S. 379-381

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ISSN: 1432-1041

Keywords: Key words Nitroglycerin; transdermal nitrate ; pharmacokinetics ; patch renewal ; exercise test

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Objective: We examined whether nitroglycerin (glyceryl trinitrate, GTN) patch treatment for 24 h could induce local cutaneous changes that impaired drug delivery and clinical efficacy. Methods: Twenty angina patients were exercise-tested after 2 and 24 h of treatment and then 2 h after patch renewal. The patch was either renewed on a new skin location or on the previous application site in a randomised, double-blind, cross-over protocol. GTN plasma concentrations and finger plethysmography were obtained before and after each exercise test. Results and conclusions: The clinical efficacy, the effect seen on plethysmography and the GTN plasma concentrations tended to increase after patch renewal, regardless of the application site of the renewed patch. Hence, cutaneous changes of clinical importance could not be demonstrated.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002280050304

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Lack of interaction between meloxicam and warfarin in healthy volunteers (1997)

Türck, D. ; Su, C. A. P. F. ; Heinzel, G. ; [et al.]

Springer

European journal of clinical pharmacology 51 (1997), S. 421-425

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ISSN: 1432-1041

Keywords: Key words Warfarin ; Meloxicam ; interaction ; pharmacokinetics ; protein binding

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Objective: The effect of multiple oral doses of meloxicam 15 mg on the pharmacodynamics and pharmacokinetics of warfarin was investigated in healthy male volunteers. Warfarin was administered in an individualized dose to achieve a stable reduction in prothrombin times calculated as International Normalized Ratio (INR) values. Then INR- and a drug concentration-time profile was determined. For the interaction phase, meloxicam was added for 7 days and then INR measurements and the warfarin drug profiles were repeated for comparison. Overall, warfarin treatment lasted for 30 days. Results: Warfarin and meloxicam were well tolerated by healthy volunteers in this study. Thirteen healthy volunteers with stable INR values entered the interaction phase. Prothrombin times, expressed as mean INR values, were not significantly altered by concomitant meloxicam treatment, being 1.20 for warfarin alone and 1.27 for warfarin with meloxicam cotreatment. R- and S-warfarin pharmacokinetics were similar for both treatments. Geometric mean (% gCV) AUCSS values for the more potent S-enantiomer were 5.07 mg · h · l−1 (27.5%) for warfarin alone and 5.64 mg · h · l−1 (28.1%) during the interaction phase. Respective AUCSS values for R-warfarin were 7.31 mg · h · l−1 (43.8%) and 7.58 mg · h · l−1 (39.1%). Conclusion: The concomitant administration of the new non-steroidal anti-inflammatory drug (NSAID) meloxicam affected neither the pharmacodynamics nor the pharmacokinetics of a titrated warfarin dose. A combination of both drugs should nevertheless be avoided and, if necessary, INR monitoring is considered mandatory.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002280050224

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How to predict carboplatin clearance from standard morphological and biological characteristics in obese patients (1997)

Bénézet, S. ; Guimbaud, R. ; Chatelut, E. ; [et al.]

Springer

Annals of oncology 8 (1997), S. 607-609

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ISSN: 1569-8041

Keywords: carboplatin ; dose adaptation ; ideal weight ; obesity ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Background: We previously proposed a formula to predict carboplatinclearance (CL) from four patient characteristics: plasma creatinine level,body weight, age, and sex (J Natl Cancer Inst 1995; 87: 573). Its accuracy wasstudied in a subpopulation of obese patients. Patients and methods: Twenty-five patients (16 male and 9 female, 23 to 82years old) were studied. They were 20% to 67% (median36%) over the ideal weight which was calculated according to theLorentz equation. Their actual CL was obtained individually by the Sipharprogram. The pharmacokinetic population program NONMEM was used to determinethe best value of substitution for weight in the formula. Results: By using the actual weight, CL was significantly overpredicted (bymore than 20% for 7 of 25 patients). By using the mean value betweenthe ideal and the actual weight, a good prediction of CL was obtained: thepercentage of error ranged from −21% to +22%. Conclusion: The formula is applicable to obese patients if both ideal andactual weights are taken into account.

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URL: http://dx.doi.org/10.1023/A:1008259009500

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Carboplatin and cisplatin pharmacokinetics after intrapleural combination treatment in patients with malignant pleural effusion (1997)

Lerza, R. ; Vannozzi, M. O. ; Tolino, G. ; [et al.]

Springer

Annals of oncology 8 (1997), S. 385-391

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ISSN: 1569-8041

Keywords: carboplatin ; cisplatin ; intrapleural combination ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Background: Cisplatin (DDP) and carboplatin (CBDCA) are two of the mosteffective drugs in a locoregional approach. Since simultaneous combinedtreatment with intrapleural DDP and CBDCA has not been reported in humans, weinvestigated its use in patients with malignant effusions, focusing onpharmacokinetics. Patients and methods: The pharmacokinetics of DDP and CBDCA were studiedin 10 patients with malignant pleural effusion treated intrapleurally with acombination of DDP (60 mg/m2) and CBDCA (270mg/m2) and in additional patients who received the same dosesof drugs administered intravenously as single agents or in combination.Platinum (Pt) species originating from DDP (metabolites plus unchanged DDP)and intact CBDCA in plasma and pleural fluid ultrafiltrates were measured bymeans of high performance liquid chromatography and atomic absorptionspectrometry. Results: Both in the plasma and pleural fluid, the total levels of free Ptrepresented the additive result of the individual concentrations of CBDCA andPt-species derived from DDP. After intrapleural combination, highpleural-plasma ratios of the peak concentrations and AUCs were observed bothfor CBDCA and DDP-derived Pt species, highlighting a distinct localpharmacological advantage. However, the Pt species originating from DDP wereabsorbed more rapidly from the pleural cavity than CBDCA (Ka= 86 × 10-3 vs. 37 ×10-3 min-1, P 〈 0.05).Intrapleural combination of CBDCA and DDP produced therapeutic plasma levelsof reactive (free) DDP species and increased the extent of their residencetime (MRT) compared with single intravenous DDP treatment [peak concentration:1.1 ± 0.1 (SD) vs. 1.6 ± 0.2 µg/ml; MRT: 5.2 ± 1.9vs. 0.5 ± 0.06 h]. Furthermore, the plasma AUC of free CBDCA afterintrapleural combined treatment (2.1 ± 0.5 mg/ml × min) wassimilar to that after intravenous administration of CBDCA alone (2.1 ±0.2 mg/ml × min). The intrapleural treatment was well tolerated by allpatients. Toxicity consisted of mild nausea and vomiting (grade 1–2according to the WHO scale) in four patients. Myelosuppression (grade1–2) was remarkable only in two heavily pretreated patients. No evidenceof recurrence of the pleural effusion was observed in six patients (completeresponse), while an asymptomatic minimal fluid reaccumulation not requiringdrainage (partial response) was observed in four patients. Conclusions: The pharmacologic results seem to exclude a pharmacokineticinteraction between CBDCA and DDP and suggest that a dose of CBDCA 2-foldhigher than that used in this study associated intrapleurally with 60mg/m2 DDP could induce an acceptable and predictablemyelosuppresion.

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URL: http://dx.doi.org/10.1023/A:1008203100410

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Cyclodextrins: Their Future in Drug Formulation and Delivery (1997)

Stella, Valentine J. ; Rajewski, Roger A.

Springer

Pharmaceutical research 14 (1997), S. 556-567

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ISSN: 1573-904X

Keywords: cyclodextrins ; drug formulation ; drug delivery ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Since their discovery, cyclodextrins and their ability to form inclusion complexes have fascinated chemists, formulators and recently, entrepreneurs. This mini-review has as its objective, a critical assessment of the current status of cyclodextrins in the formulation and delivery of pharmaceuticals and commentary on their potential future uses. The emphasis will be on answers to common questions often asked of pharmaceutical scientists working in this area. Why use cyclodextrins for drug solubilization and stabilization when alternative techniques are available? Why the greater interest in modified cyclodextrins and not the parent cyclodextrins? If a drug forms a strong cyclodextrin inclusion complex, how is the drug releasedin vivo? Does the injection of a cyclodextrin/drug complex alter the pharmacokinetics of the drug? Are there drug products on the market which contain cyclodextrins? What is the regulatory status of cyclodextrins? Although definitive answers to all these questions are not possible at this time, many of these questions are answerable, and educated and informed responses are possible for the rest.

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URL: http://dx.doi.org/10.1023/A:1012136608249

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Pharmacokinetic-Based Minibolus Delivery as an Alternative to Continuous Infusion for Drugs That Exhibit a Biophase Lag (1997)

Kern, Steven E. ; Westenskow, Dwayne R.

Springer

Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 191-208

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ISSN: 1573-8744

Keywords: pharmacokinetics ; pharmacodynamics ; frequency response ; biophase models ; infusion pumps

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract The presence of a biophase compartment in a pharmacokinetic model indicates that the response to an administered dose of drug is damped such that the time to peak effect occurs after the peak concentration in the bloodstream. This phenomenon, which is common to most intravenous anesthetic agents, can be exploited by a drug delivery method that administers minibolus doses of drug rather than a continuous infusion. Through analysis of the frequency response behavior of the biophase compartment, a bolus magnitude and dose frequency or interval (1/frequency) can be chosen such that the oscillation in drug effect is minimized even though the plasma concentration may be changing significantly with each supplemental dose. A pharmacokinetic and pharmacodynamic based method for calculating the bolus dose size and dosing interval is presented. The trade-off between dose interval and change in drug effect is exemplified through computer simulation of this strategy applied to delivery of the neuromuscular blocking agent pancuronium. The method provides a repetitive perturbation to the pharmacokinetic and pharmacodynamic system that can aid in model parameter identification during closed loop applications.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1025732129798

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Comparative Pharmacokinetics and Pharmacodynamics of Two Recomhinant Human Interferon Beta-la (IFNβ-la) Products Administered Intramuscularly in Healthy Male and Female Volunteers (1997)

Alam, John ; Goelz, Susan ; Rioux, Patrice ; [et al.]

Springer

Pharmaceutical research 14 (1997), S. 546-549

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ISSN: 1573-904X

Keywords: Avonex™ ; Rebif® ; interferon-beta-la ; pharmacokinetics ; pharmacodynamics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1012128406432

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Carboxyl-directed Pegylation of Brain-derived Neurotrophic Factor Markedly Reduces Systemic Clearance with Minimal Loss of Biologic Activity (1997)

Sakane, Toshiyasu ; Pardridge, William M.

Springer

Pharmaceutical research 14 (1997), S. 1085-1091

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ISSN: 1573-904X

Keywords: pegylation ; pharmacokinetics ; blood-brain barrier

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. Brain-derived neurotrophic factor (BDNF) was modified by carboxyl-directed protein pegylation in order to both retain biologic activity of the neurotrophin and reduce the rate of systemic clearance of this cationic protein in vivo. Since the modification of surface lysine residues of neurotrophins results in loss of biologic activity, the present studies examine the feasibility of placing polyethyleneglycol (PEG) polymers on carboxyl residues of surface glutamate or aspartate residues of BDNF. Methods. PEG molecules with terminal hydrazide (Hz) moieties of molecular weight 2,000 (PEG2000-Hz) or 5,000 (PEG5000-Hz) Daltons were coupled to BDNF carboxyls using carbodiimide. Results. The systemic clearances of the BDNF-PEG2000 and BDNF-PEG5000 were reduced 67% and 91%, respectively, compared to unconjugated BDNF. The brain volume of distribution (VD) of BDNF-PEG5000 was not significantly different from the cerebral plasma volume. Cell survival studies and TrkB auto-phosphorylation assays showed that the biologic activity of BDNF was not changed following pegylation with PEG2000, and was minimally impaired following pegylation with PEG5000. Conclusions. These experiments describe the first carboxyl-directed pegylation of a neuropeptide, and show this formulation substantially reduces the systemic distribution and elimination of the neurotrophic factor. The biologic activity of the neurotrophin is retained with carboxyl-directed pegylation.

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URL: http://dx.doi.org/10.1023/A:1012117815460

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Prednicarbate Biotransformation in Human Foreskin Keratinocytes and Fibroblasts (1997)

Gysler, Anja ; Lange, Katharina ; Korting, Hans Christian ; [et al.]

Springer

Pharmaceutical research 14 (1997), S. 793-797

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ISSN: 1573-904X

Keywords: prednicarbate ; topical glucocorticoids ; pharmacokinetics ; biotransformation ; keratinocytes ; fibroblasts

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. Evaluation of skin layer-specific prednicarbate (PC) biotransformation, possibly explaining the improved benefit/risk ratio of this topical corticosteroid in atopic dermatitis (1,2). Methods. Metabolism of PC in keratinocyte and fibroblast monolayers derived from human juvenile foreskin was evaluated. Drug concentration was determined by HPLC/UV-absorption. Accompanying cell viability tests (MTT-tests) were performed to exclude toxic drug effects. Results. Keratinocytes hydrolyzed the double ester PC (2.5 × 10−6 M) at position 21 to the monoester prednisolone 17-ethylcarbonate (P17EC) which nonenzymatically transformed to prednisolone 21-ethylcarbonate (P21EC). This metabolite was enzymatically cleaved to prednisolone (PD), the main biotransformation product at 24 hours. Fibroblasts, however, showed a distinctively lower enzyme activity. Both, PC and P17EC (or rather P21EC) were hydrolyzed to a minor extent only. The biotransformation pathway, however, was the same. When P17EC was added separately, it transformed to P21EC and again was cleaved by keratinocytes to a much higher extent. Despite of the rather high glucocorticoid concentration MTT-tests proved a non-disturbed cell viability and proliferation rate. Conclusions. Extrapolating our results to the in-vivo situation, topically applied PC may be metabolized by epidermal cells during skin penetration. A complex mixture of compounds reaches the dermis, whose fibroblasts are barely able to metabolize the steroids. Since skin atrophy is less pronounced with PC as compared to conventional halogenated glucocorticoids, less potent PC metabolites appear to be the dominant species in the dermis.

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URL: http://dx.doi.org/10.1023/A:1012162708675

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Modeling in Frequency Domain Used for Assessment of In Vivo Dissolution Profile (1997)

Ďurišová, Mária ; Dedík, Ladislav

Springer

Pharmaceutical research 14 (1997), S. 860-864

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ISSN: 1573-904X

Keywords: aspirin ; pharmacokinetics ; dissolution ; weighting function ; convolution ; bioequivalence

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. To present a model-dependent approach for the assessment of the in vivo drug dissolution profile based on in vitrodata for the multiple unit dosage form, as an alternative to the numerical method proposed in the study by Hayashi et al, Pharm. Res. 12:1333−1337 (1995). Methods. The data for aspirin granules administered to healthy subjects obtained in the above mentioned study were re-evaluated. The subject dissolution system was considered to consist of two subsystems connected in series, i.e. the subsystem describing the gastric-emptying process and the subsystem describing the intestinal dissolution process. The frequency response method was used to model the subject dissolution system. Results. The model in vivodissolution profile of aspirin, assessed as the integral of the model weighting function of the subject dissolution system, was in agreement with the in vivo cumulative absorption profile calculated by the Wagner-Nelson method. Conclusions. Comparison of dynamic properties of the subject dissolution system with the subsystem describing the gastric-emptying process yielded quantitative confirmation of the decisive role of the gastric-emptying process in the in vivodrug dissolution after administration in the multi unit dosage form.

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URL: http://dx.doi.org/10.1023/A:1012139530965

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The Disposition of Valproyl Glycinamide and Valproyl Glycine in Rats (1997)

Blotnik, Simcha ; Bergman, Felix ; Bialer, Meir

Springer

Pharmaceutical research 14 (1997), S. 873-878

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ISSN: 1573-904X

Keywords: valproyl glycinamide ; valproyl glycine ; pharmacokinetics ; brain and liver distribution

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. To investigate the disposition of valproyl glycinamide and valproyl glycine in rats and to compare it with that of valproic acid (VPA) and valpromide which were studied previously. Methods. The study was carried out by monitoring the brain and liver levels of valproyl glycinamide and valproyl glycine (as a function of time after iv dosing) in addition to the regular pharmacokinetic (PK) monitoring of plasma and urine levels of these compounds. Results. The following PK parameters were obtained for valproyl glycinamide and valproyl glycine, respectively: clearance, 7.1 and 16 ml/ min/kg; volume of distribution (Vss), 0.78 and 0.41 1/kg; half-life, 1.1 and 0.37 h; and mean residence time, 1.8 and 0.4 h. The ratios of AUCs of valproyl glycinamide of liver to plasma and brain to plasma were 0.70 and 0.66, respectively. The ratios of the AUCs of valproyl glycine of liver to plasma and brain to plasma were 0.19 and 0.02, respectively. Conclusions. Valproyl glycinamide distributes better in the brain than VPA, a fact which may contribute to its better anticonvulsant activity. Valproyl glycine was barely distributed in the brain, a fact which may explain its lack of anticonvulsant activity. In addition to the liver, the brain was found to be a minor metabolic site of the biotransformation of valproyl glycinamide to valproyl glycine.

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URL: http://dx.doi.org/10.1023/A:1012143631873

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Assessment of Dose Proportionality, Absolute Bioavailability, and Immunogenicity Response of CTLA4Ig (BMS-188667), a Novel Immunosuppressive Agent, Following Subcutaneous and Intravenous Administration to Rats (1997)

Srinivas, Nuggehally R. ; Shyu, Wen Chyi ; Weiner, Russell S. ; [et al.]

Springer

Pharmaceutical research 14 (1997), S. 911-916

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ISSN: 1573-904X

Keywords: CTLA4Ig ; intravenous ; subcutaneous ; pharmacokinetics ; immunogenicity ; rats

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. The objectives of this study were: to delineate the pharmacokinetics of CTLA4Ig in rats after single and multiple intravenous (IV) and subcutaneous (SC) doses; to assess the relationship of the pharmacokinetic parameters of CTLA4Ig vs dose; to calculate the SC absolute bioavailability; and to assess the antibody response of CTLA4Ig. Methods. A total of 48 (24 male and 24 female) Sprague Dawley rats were divided into eight treatments with 3 rats per gender in each group: a single dose of 10, 80, or 200 mg/kg of CTLA4Ig given either IV or SC and a repeated dose of 10 mg/kg (once every other day for 7 doses over 13 days) given either SC or IV. Serial blood samples were collected up to 43 days after single dose administration and up to 50 days following the administration of the last multiple dose on day 13. The serum concentration of CTLA4Ig and anti-CTLA4Ig antibodies were measured using ELISA assays. Results. After single IV doses, Cmax and AUCinf increased in a dose proportional manner; CL appeared to be dose independent, while both Vss and T1/2 increased as the administered dose increased. Following single SC doses, Cmax and AUCinf increased in a linear manner but not proportionally; mean Tmax values were prolonged but similar among the three dose levels, while T1/2 increased as the administered dose increased. The absolute SC bioavailability of CTLA4Ig decreased as the dose increased from 10 (62.5%), 80 (55.7%), and 200 mg/kg (41.1%). Comparison of the AUCtau values between the first and last doses suggested an accumulation (3.1−4.7) of CTLA4Ig. However, regardless of the route of dosing, AUCtau after the last dose were comparable to AUCinf values following the single dose. Anti-CTLA4Ig antibodies were detected at the 10 mg/kg dose level after single or multiple doses for both routes of administration. However, regardless of single or multiple doses, antibody titers were relatively greater for the SC compared to the IV administration. Conclusions. The key findings of this study were: (i) the elimination characteristics of CTLA4Ig were comparable between the SC and IV routes; (ii) the repeated dosing did not alter the pharmacokinetics of CTLA4Ig; (iii) the SC absolute bioavailability tended to decrease as the administered dose increased; and (iv) a greater formation of anti-CTLA4Ig antibodies was observed after SC compared to IV at a single 10 mg/kg dose level; however, after multiple dosing, the formation of antibodies from either of the two routes was relatively slower, and (v) during the study period, no antibodies were observed at either the 80 or 200 mg/kg dose levels regardless of the route of administration.

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URL: http://dx.doi.org/10.1023/A:1012156001831

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Pharmacokinetic Model of Ascorbic Acid in Healthy Male Volunteers During Depletion and Repletion (1997)

Graumlich, James F. ; Ludden, Thomas M. ; Conry-Cantilena, Cathy ; [et al.]

Springer

Pharmaceutical research 14 (1997), S. 1133-1139

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ISSN: 1573-904X

Keywords: ascorbic acid ; pharmacokinetics ; human ; models— theoretical ; models—nonlinear ; bioavailability ; ascorbic acid deficiency

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. To develop a new pharmacokinetic model for ascorbic acid (vitamin C) since no previously published model describes ascorbic acid absorption and disposition over a broad physiologic range of doses and plasma concentrations. Methods. A new model was developed through exploratory simulations. The model was fitted to pharmacokinetic data obtained from seven healthy volunteers who underwent ascorbic acid depletion then gradual repletion. Concentrations of ascorbic acid were measured in plasma and urine. Final pharmacokinetic model parameter estimates were obtained using nonlinear regression analysis. Results. The new model included saturable absorption, distribution and renal tubular reabsorption parameters. The model described ascorbic acid concentrations in plasma, cells, and urine during depletion and gradual repletion phases with a residual error less than 15%. Conclusions. The model was useful for obtaining a new understanding of the likely causes for the complex concentration-time profile observed during gradual repletion. At doses of 200 to 2500 mg per day, the plateau in pre-dose concentrations is largely due to apparent saturation of tissue uptake and less a function of oral bioavailability and renal excretion than previously thought.

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URL: http://dx.doi.org/10.1023/A:1012186203165

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Aspects of the Pharmacokinetics of Doxycycline Given to Healthy and Pneumonic East African Dwarf Goats by Intramuscular Injection (1997)

Ole-Mapenay, I.M. ; Mitema, E.S. ; Maitho, T.E.

Springer

Veterinary research communications 21 (1997), S. 453-462

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ISSN: 1573-7446

Keywords: doxycycline ; goats ; pharmacokinetics ; pneumonia ; treatment

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Ole-Mapenay, I.M., Mitema, E.S. and Maitho, T.E., 1997. Aspects of the pharmacokinetics of doxycycline given to healthy and pneumonic East African dwarf goats by intramuscular injection. Veterinary Research Communications, 21 (6), 453-462 The effect of experimentally induced Pasteurella haemolytica pneumonia on the pharmacokinetics of doxycycline (Doxycen Retard) administered intramuscularly was studied in seven East African dwarf goats. The study was conducted in two consecutive phases, separated by a washout period of four weeks. The experimental infection, induced by intratracheal administration of 5 ml of 107 to 109 cfu/ml of Pasteurella haemolytica, produced a temperature rise, depression and laboured breathing within 6-12 days after inoculation. The concentrations of doxycycline in the serum were determined by a quantitative microbiological assay using an agar-gel diffusion method employing Bacillus cereus var mycoides (ATCC 11778) as the test organism, with a level of detectability of approximately 0.05 µg/ml. The concentration-time curve of doxycycline in the serum after intramuscular injection of 20 mg/kg bodyweight of the long-acting formulation before and after experimental infection was adequately described by a one-compartment open model. The maximum serum concentrations (Cmax) of doxycycline were lower in pneumonic goats than in healthy goats (3.87 ± 0.52 and 5.56 ± 0.213 µg/ml, respectively), suggesting an increased distribution volume in the peripheral compartment. The mean ± SEM absorption rate (ka) before infection (1.13 ± 0.02 h-1) was smaller than that after infection (8.23 ± 3.81 h-1), but the difference was not significant. The apparent elimination half-life (t1/2β) (24.51 ± 0.02 h) after infection was significantly increased (p 〈 0.05), while the corresponding rate constant (β) was decreased (p 〈 0.01). The absorption half-life (t1/2α) (0.137 ± 0.03 h) was significantly decreased (p 〈 0.01) after infection. The distribution volume (Vd(β)) was significantly increased after infection (p 〈 0.05). It is concluded that, although experimental infection had an effect on the disposition kinetics of doxycycline, this was not sufficiently pronounced to require alteration of the dosage during disease.

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URL: http://dx.doi.org/10.1023/A:1005863520483

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Pharmacokinetics of cyclosporine in pediatric long-term liver transplant recipients converted from Sandimmun to Neoral (1997)

Melter, M. ; Rodeck, Burkhard ; Kardorff, Rüdiger ; [et al.]

Springer

Transplant international 10 (1997), S. 419-425

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ISSN: 1432-2277

Keywords: Key words Cyclosporin ; conversion ; liver transplantation ; Conversion ; cyclosporin ; liver transplantation ; Liver transplantation ; conversion ; cyclosporin ; Pediatric liver transplantation ; pharmacokinetics ; Pharmacokinetics ; pediatric liver transplantation

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Absorption of cyclosporin from the microemulsion formulation Neoral is less variable than from Sandimmun. Because of a lack of data in pediatric liver transplant recipients, the pharmacokinetic profiles with Sandimmun and Neoral were compared in a conversion study. Thirty-eight children with stable graft function were converted 2–12.3 years post-transplant at a 1:1 ratio. The trough-level (Cmin) with Neoral was 123 ± 39 ng/ml versus 134 ± 29 ng/ml with Sandimmun (P = NS), the area under the time-concentration curve (AUC) was 3325 ± 1125 ng*h/ml versus 2423 ± 846 ng*h/ml (P 〈 0.001), the peak concentration (Cmax) was 650 ± 280 ng/ml versus 337 ± 142 ng/ml (P 〈 0.001), and the median time to Cmax was 2 h (range 0.5–3 h) versus 4 h (range 1–8 h; P 〈 0.05). The weak correlation between Cmin and AUC with Sandimmun (r = 0.5; P = NS) was improved by using Neoral (r = 0.7; P 〈 0.001). The best predictor of AUC was the 2-h concentration (C2 h) of Neoral (r = 0.9; P 〈 0.001). Increased absorption and a more predictable pharmacokinetic profile with Neoral permit safer therapeutic monitoring in children. The exclusive measurement of Neoral-C2 h allows one to estimate drug exposure with high precision ( 〉 90 %).

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URL: http://dx.doi.org/10.1007/s001470050080

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Blood-retina barrier permeability is independent of trace substance lipid solubility in retinitis pigmentosa and in the healthy eye (1997)

Larsen, Michael ; Engler, Claus B ; Haim, Marianne ; [et al.]

Springer

International ophthalmology 21 (1997), S. 229-234

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ISSN: 1573-2630

Keywords: blood-retina barrier ; fluorescein ; fluorescein glucuronide ; retina ; vitreous fluorometry ; fluorophotometry ; retinitis pigmentosa ; healthy subjects ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Differential ocular spectrofluorometry was used toassess the passive permeability of the blood-retinabarrier in healthy subjects and in patients withretinitis pigmentosa by determination of the rate ofinward leakage of fluorescein and fluoresceinglucuronide after intravenous injection offluorescein.In five healthy subjects we found permeabilities of1.3 (0.6–2.8) nm/s [log-mean (range)] for fluoresceinand 1.3 (0.6–3.1) nm/s for fluorescein glucuronide.Six patients with retinitis pigmentosa all had amarkedly increased blood-retina barrier leakage, withinward permeabilities of 8.2 (3.4–25) nm/s forfluorescein and 8.2 (5.6–27) nm/s for fluoresceinglucuronide.Since no detectable difference was found between thepermeabilities of the two tracers the passive permeability of the blood-retina barrier appears to beindependent of the 18-fold difference in lipidsolubility between the two tracers, both in retinitispigmentosa and in healthy subjects. Presumably, thestructural substrate for leakage of small hydrophilicmolecules through the blood-retina barrier is awater-filled pore, since diffusion through lipidcellular membranes would favor fluorescein over itsmore water soluble glucuronide.

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URL: http://dx.doi.org/10.1023/A:1006044107353

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Enhanced Plasma Availability of the Metabolites of Albendazole in Fasted Adult Sheep (1997)

Lifschitz, A. ; Virkel, G. ; Mastromarino, M. ; [et al.]

Springer

Veterinary research communications 21 (1997), S. 201-211

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ISSN: 1573-7446

Keywords: anthelmintic ; albendazole ; fasting ; pharmacokinetics ; sheep

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Lifschitz, A., Virkel G., Mastromarino, M. and Lanusse C., 1997. Enhanced plasma availability of the metabolites of albendazole in fasted adult sheep. Veterinary Research Communications, 21 (3), 201-211 The influence of fasting prior to treatment and of dosing rate on the plasma availability and disposition kinetics of albendazole (ABZ) and its sulphoxide (ABZSO) and sulphone (ABZSO2) metabolites was studied in adult sheep grazing on pasture. A micronized suspension of ABZ was administered orally at either 7.5 mg/kg (group A) or 11.3 mg/kg (group C) to sheep fed ad libitum, and at 7.5 mg/kg to sheep subjected to a 24 h fasting period prior to treatment (group B). Blood samples were taken serially over 96 h after treatment, and the plasma was analysed for ABZ and its metabolites by high-performance liquid chromatography. ABZSO and ABZSO2 were recovered from the plasma. Fasting induced marked modifications in the pharmacokinetic behaviour of the ABZ metabolites in sheep. An extended absorption process, with a delayed peak concentration in the plasma, was observed for both metabolites in the fasted sheep. Significantly higher area under the curve (AUC) and peak plasma concentration (Cmax) values were obtained for both metabolites in the fasted animals compared to those fed ad libitum. Delayed elimination with prolonged detection in plasma was also observed in the fasted sheep. Treatment with ABZ at 7.5 mg/kg in the starved animals resulted in bioequivalence to the administration of the compound at a 50% higher dose rate (11.3 mg/kg) in the fed animals. It is suggested that fasting enhances ABZ dissolution and absorption by delaying its passage down the digestive tract.

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URL: http://dx.doi.org/10.1023/A:1005832412415

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Some Pharmacokinetic Parameters of Oxfendazole in Sheep (1997)

Soraci, A.L. ; Mestorino, N. ; Errecalde, J.O.

Springer

Veterinary research communications 21 (1997), S. 283-287

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ISSN: 1573-7446

Keywords: oxfendazole ; pharmacokinetics ; sheep ; sulphone

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Soraci, A.L., Mestorino, N. and Errecalde, J.O., 1997. Some pharmacokinetic parameters of oxfendazole in sheep. Veterinary Research Communications, 21 (4), 283-287

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URL: http://dx.doi.org/10.1023/A:1005843010696

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Effects of Diet and Species on the Pharmacokinetics of Fenbendazole in Cattle (1997)

Knox, M.R. ; Steel, J.W.

Springer

Veterinary research communications 21 (1997), S. 37-43

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ISSN: 1573-7446

Keywords: anthelmintic ; benzimidazole ; cattle ; diet ; fenbendazole ; pharmacokinetics ; species

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Knox, M.R. and Steel, J.W., 1997. Effects of diet and species on the pharmacokinetics of fenbendazole in cattle. Veterinary Research Communications, 21 (1), 37-43. The plasma concentration profiles of fenbendazole (FBZ), FBZ-sulphoxide (OFZ) and FBZ-sulphone were measured following intraruminal administration of FBZ at 7.5 mg/kg bodyweight in Bos taurus and B. indicus cattle offered three different diets: 100% wheaten chaff, 100% lucerne, and a 50:50 mix of these two diets. No differences between the species were apparent except for a longer time to peak plasma concentration for OFZ in the B. taurus steers fed 100% wheaten chaff. Cattle fed wheaten chaff alone gave greater areas under the concentration-time curve and longer persistence for all metabolites than when the same cattle were fed the other diets. It is concluded that the reduced rate of passage of digesta on lower-quality fibrous diets allows greater time for absorption of FBZ and its metabolites from the gut, thereby increasing systemic availability.

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URL: http://dx.doi.org/10.1023/B:VERC.0000009699.60051.e1

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The Effects of the Method of Calculation on the Evaluation of the Pharmacokinetic Parameters of Oxytetracycline After Intravenous Administration to Calves (1997)

Errecalde, J.O. ; Mestorino, N. ; Mariño, E.L.

Springer

Veterinary research communications 21 (1997), S. 273-281

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ISSN: 1573-7446

Keywords: calculations ; calves ; intravenous ; oxytetracycline ; pharmacokinetics ; plasma ; tissue

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Errecalde, J.O., Mestorino, N. and Mariño, E.L., 1997. The effects of the method of calculation on the evaluation of the pharmacokinetic parameters of oxytetracycline after intravenous administration to calves. Veterinary Research Communications, 21 (4), 273-281 The aim of this study was to assess the differences in the values of the pharmacokinetic parameters attributable to the use of either linear or nonlinear regression analysis and to find the effect of weighting schemes on these differences. Six calves received 20 mg/kg oxytetracycline i.v. Blood samples were drawn during 72 h. The assay of the drug was performed microbiologically. A bicompartmental pharmacokinetic model was used, kinetic analysis being carried out by linear regression (LR) and by weighted least-squares nonlinear regression (WLSNLR). Statistical analysis included a test for normality, the Kruskall-Wallis test and ANOVA with log transformation. The A0, α and B0 did not show any statistically significant differences attributable to the mathematical method used. On the other hand, the statistically significant differences in the β values found using the Kruskall-Wallis test and ANOVA with log transformation could be attributed to the different methods employed. ANOVA with log transformation determined statistically significant differences between the parameters obtained by linear analysis and those obtained by WLSNLR when the weighting (w) was 1. When weights were 1/x, 1/x2 or 1/√ x, no statistically significant differences were found. The optimal weighting scheme was w = 1/x2 because of a more homogeneous scatter and random distribution of residuals about the abcissa axis in a plot of weighted residuals in the ordinate versus time in the abcissa. It was concluded that the use of these different procedures can give major variations in the apparent value of β, the most important pharmacokinetic parameter. The correct selection of the weighting procedure is therefore fundamental in obtaining the best estimate of this pharmacokinetic parameter in WLSNLR.

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URL: http://dx.doi.org/10.1023/A:1005890926626

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The effect of water deprivation on the pharmacokinetics of antipyrine and sulphadimidine following intravenous administration in Nubian goats (1997)

Elsheikh, H.A. ; Osman, I.A.M. ; Abdullah, A.S.

Springer

Veterinary research communications 21 (1997), S. 587-597

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ISSN: 1573-7446

Keywords: antipyrine ; dehydration ; goats ; pharmacokinetics ; sulphadimidine

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract The effect of water deprivation on the pharmacokinetic parameters of antipyrine and sulphadimidine in the Nubian goat was studied. Water deprivation, to a level of dehydration at which the animals lost an average of 7.5% body weight, resulted in a significant reduction in antipyrine clearance (p〈0.05), and a consequently increased AUC value (p〈0.05). No effect was observed on the distribution parameters of the drug. In dehydrated animals which had lost an average of 10% or 12.5% of their body weight owing to water deprivation, significant changes were found in the distribution and elimination pharmacokinetic parameters of antipyrine and sulphadimidine. The volume of distribution was significantly decreased, resulting in elevated plasma levels for the two drugs compared to normally watered animals. Significant decreases in clearance and subsequent prolongation of the elimination half-lives were observed during these periods of water deprivation. These changes in the disposition kinetics of the two drugs may be attributed to the loss of total body water and extracellular fluids and changes in the liver and kidney functions taking place during dehydration.

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URL: http://dx.doi.org/10.1023/A:1005975016275

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Pharmacokinetics of reboxetine enantiomers in the dog (1997)

Frigerio, E. ; Benecchi, A. ; Brianceschi, G. ; [et al.]

New York, NY [u.a.] : Wiley-Blackwell

Chirality 9 (1997), S. 303-306

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ISSN: 0899-0042

Keywords: reboxetine ; enantiomers ; dog ; pharmacokinetics ; HPLC determination ; Chemistry ; Organic Chemistry

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Chemistry and Pharmacology

Notes: Reboxetine, (RS)-2-[(RS)-α-(2-ethoxyphenoxy)benzyl]morpholine methanesulphonate, is a racemic compound and consists of a mixture of the (R,R)- and (S,S)-enantiomers. The pharmacokinetics of reboxetine enantiomers were determined in a crossover study in three male beagle dogs. Each animal received the following oral treatments, separated by 1-week washout period: 10 mg/kg reboxetine, 5 mg/kg (R,R)- and 5 mg/kg (S,S)-. Plasma and urinary levels of the reboxetine enantiomers were monitored up to 48 h post-dosing using an enantiospecific HPLC method with fluorimetric detection (LOQ: 1.1 ng/ml in plasma and 5 ng/ml in urine for each enantiomer). After reboxetine administration mean tmax was about 1 h for both enantiomers. Cmax and AUC were about 1.5 times higher for the (R,R)- than for the (S,S)-enantiomer, mean values ± SD being 704 ± 330 and 427 ± 175 ng/ml for Cmax and 2,876 ± 1,354 and 1,998 ± 848 ng.h/ml for AUC, respectively. No differences between the (R,R)- and (S,S)-enantiomers were observed in t½ (3.9 h). Total recovery of the two enantiomers in urine was similar, the Ae (0-48 h) being 1.3 ± 0.7 and 1.1 ± 0.7% of the enantiomer dose for the (R,R)- and the (S,S)-enantiomers, respectively. No marked differences in the main plasma pharmacokinetic parameters were found for either enantiomer on administration of the single enantiomers or reboxetine. No chiral inversion was observed after administration of the separate enantiomers, as already observed in humans. Chirality 9:303-306, 1997. © 1997 Wiley-Liss, Inc.

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Enantioselective determination of the hydroxylated metabolites of mexiletine in human plasma (1997)

Lanchote, Vera Lúcia ; Bonato, Pierina Sueli ; Cesarino, Evandro José ; [et al.]

New York, NY [u.a.] : Wiley-Blackwell

Chirality 9 (1997), S. 732-738

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ISSN: 0899-0042

Keywords: hydroxymethylmexiletine ; p-hydroxymexiletine ; circular dichroism ; diastereomer HPLC ; validation ; plasma ; pharmacokinetics ; Chemistry ; Organic Chemistry

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Chemistry and Pharmacology

Notes: Pre-column derivatization with o-phthaldialdehyde and N-acetyl-l-cysteine was used for liquid-chromatographic diastereomeric resolution of p-hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM), metabolites of mexiletine formed by aromatic and aliphatic hydroxylation, respectively. The resulting diastereomeric derivatives were resolved on a C18 column and monitored by fluorescence detection. The diastereomeric elution order for both metabolites was determined on the basis of the circular dichroism spectra of each eluted fraction. Plasma samples (500 μl) showed recoveries greater than 75% for both the metabolites. Calibration curves in plasma samples were linear over the concentration ranges 10-500 and 20-1,000 ng/ml for each enantiomer of PHM and HMM, respectively. The limits of quantitation were found to be 10.0 and 5.0 ng/ml for both enantiomers of PHM and HMM. The within-day and between-day coefficients of variation were less than 10%. The assay was shown to be suitable for a pharmacokinetic study performed in a patient with ventricular arrhythmias following the short-term oral treatment of 200 mg t.i.d. of racemic mexiletine hydrochloride. Chirality 9:732-738, 1997. © 1997 Wiley-Liss, Inc.

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Stereoselective disposition and chiral inversion of KE-298, a new antirheumatic drug, in rats (1997)

Yoshida, H. ; Kohno, Y. ; Endo, H. ; [et al.]

New York, NY [u.a.] : Wiley-Blackwell

Chirality 9 (1997), S. 22-28

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ISSN: 0899-0042

Keywords: pharmacokinetics ; metabolism ; stereoselectivity ; protein binding ; binding site ; displacement ; metabolic chiral inversion ; chiral HPLC ; Chemistry ; Organic Chemistry

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Chemistry and Pharmacology

Notes: The present study was an attempt to elucidate the relationship between stereoselective pharmacokinetics and protein binding of KE-298 and its active metabolites, deacetyl-KE-298 (M-1) and S-methyl-KE-298 (M-2). Metabolic chiral inversion was also investigated. The levels of unchanged KE-298 in plasma after oral administration of (+)-(S)-KE-298 to rats were lower than those of (-)-(R)-KE-298, whereas the levels of M-1 and M-2 after administration of (+)-(S)-KE-298 were higher than after (-)-(R)-KE-298. In vitro, rat plasma protein binding of (+)-(S)-KE-298 was lower than that of (-)-(R)-KE-298. In contrast, the binding of (+)-(S)-M-1 and (+)-(S)-M-2 was higher than that of (-)-(R)-M-1 and (-)-(R)-M-2. Displacement studies revealed that the (+)-(S) and (-)-(R)-enantiomers of KE-298 and their metabolites bound to the warfarin binding site on rat serum albumin. These results suggest that the stereoselective plasma levels in KE-298 and its metabolites were closely related to enantiomeric differences in protein binding, attributed to quantitative differences in binding to albumin rather than to the different binding sites. Unidirectional chiral inversion was detected after oral administration of either (-)-(R)-KE-298 or (-)-(R)-M-2 to rats both yielding (+)-(S)-M-2. Chirality 9:22-28, 1997 © 1997 Wiley-Liss, Inc.

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Unusual central nervous system toxicity in a phase I study of N1N11diethylnorspermine in patients with advanced malignancy (1997)

Creaven, Patrick J. ; Perez, Raymond ; Pendyala, Lakshmi ; [et al.]

Springer

Investigational new drugs 15 (1997), S. 227-234

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ISSN: 1573-0646

Keywords: diethylnorspermine ; phase I ; pharmacokinetics ; CNS toxicity

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract The objectives of this study were to determine the dose limiting toxicity (DLT) and other major toxicities, the maximum tolerated dose (MTD) and the human pharmacokinetics of N1N11diethylnorspermine (DENSPM), a new polyamine analog which in experimental systems inhibits the biosynthesis of intracellular polyamines and promotes their degradation by inducing the enzyme spermine/spermidine N-acetyl transferase. These objectives were incompletely achieved because of the occurrence of an unusual syndrome of acute central nervous system toxicity which forms the basis of the present report. Fifteen patients with advanced solid tumors were entered into a phase I study of DENSPM given by a 1h i.v. infusion every 12h for 5 days (10 doses). The starting dose was 25 mg/m2/day (12.5 mg/m2/dose) with escalation by a modified Fibonacci search. Doses of 25 and 50 mg/m2/day were tolerated with only minor side effects of facial flushing, nausea, headache and dizziness (all grade I). At doses of 83 and 125 mg/m2/day, a symptom complex of headache, nausea and vomiting, unilateral weakness, dysphagia, dysarthria, numbness, paresthesias, and ataxia, was seen in 3 patients, one after 2 courses of 83 and 2 after 1 course of 125 mg/m2/day. This syndrome occurred after drug administration was complete and the patients had returned home. Lesser CNS toxicity was seen in 2 other patients at lower daily doses. Preliminary pharmacokinetics of DESPM measured in plasma by HPLC in 8 patients showed linearity with dose and a rapid plasma decay with a t2 of 0.12h. We conclude that great caution is warranted in administering DENSPM on this schedule at doses of ≥ 83 mg/m2/day.

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URL: http://dx.doi.org/10.1023/A:1005827231849

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Depsipeptide (FR901228, NSC-630176) pharmacokinetics in the rat by LC/MS/MS (1997)

Chan, Kenneth K. ; Bakhtiar, Ray ; Jiang, Chun

Springer

Investigational new drugs 15 (1997), S. 195-206

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ISSN: 1573-0646

Keywords: depsipeptide ; electrospray LC/MS/MS ; pharmacokinetics ; oral absorption

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Depsipeptide, a cyclic peptide (FR), isolated from Chrombacterium violaceum strain WB968 by Fujisawa Company during a screening program for anti-oncogene agents, possesses potent antitumor activity against human tumor cell lines and xenografts. This compound has been selected for preclinical and early clinical development by the National Cancer Institute. The pharmacokinetics and oral bioavailability of this depsipeptide in the rat were investigated in the present study. A sensitive and specific electrospray LC-tandem mass spectrometry method was first developed and validated for the analysis of this depsipeptide in plasma using t-boc-α-d-glutamic acid benzyl ester as the internal standard. The routine sensitivity limit was 1 or 10 ng/ml using 1.0 or 0.1 ml of plasma sample. The within-run CV values were 11.8, 17.9, 11.0, and 5.0% at 1, 10, 100, and 500 ng/ml levels, respectively, with corresponding accuracy of 94.4, 109, 95, and 97% (all n=6). A formulation based on ethanol, normal saline and PEG400 was then developed and Fischer rats were given this formulated drug separately by intravenous and oral route. Plasma drug concentrations were measured by this method and pharmacokinetics were analyzed by the standard techniques. Plasma concentration-time profiles were found to follow a biexponential decline with a mean terminal t1/2 of 97 min and mean total clearance (CLt) of 425.3 ml/min/kg following iv dosing at 10 mg/kg. Following oral dosing at 50 mg/kg, the peptide was absorbed but produced erratic drug levels also with a bioavailability of 15.6%. Thus, active plasma concentrations can be produced up to 3 hrs in the rat following a single dose at 10 mg/kg and the peptide represents one of the very few orally absorbed peptides reported.

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URL: http://dx.doi.org/10.1023/A:1005847703624

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Applications of primary human hepatocytes in the evaluation of pharmacokinetic drug-drug interactions: Evaluation of model drugs terfenadine and rifampin (1997)

Li, A.P. ; Jurima-Romet, M.

Springer

Cell biology and toxicology 13 (1997), S. 365-374

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ISSN: 1573-6822

Keywords: drug development ; drug interactions ; drug metabolism ; drug toxicity ; human hepatocytes ; pharmacokinetics ; rifampin ; terfenadine

Source: Springer Online Journal Archives 1860-2000

Topics: Biology , Medicine

Notes: Abstract The utility of primary human hepatocytes in the evaluation of drug-drug interactions is being investigated in our laboratories. Our initial approach was to investigate whether drug-drug interactions observed in humans in vivo could be reproduced in vitro using human hepatocytes. Two model drugs were studied: terfenadine and rifampin, representing compounds subjected to drug-drug interactions via inhibitory and induction mechanisms, respectively. Terfenadine was found to be metabolized by human hepatocytes to C-oxidation and N-dealkylation products as observed in humans in vivo. Metabolism by human hepatocytes was found to be inhibited by drugs which are known to be inhibitory in vivo, Ki values for the various inhibitors were derived from the in vitro metabolism data, resulting in the following ranking of inhibitory potency: For the inhibition of C-oxidation, ketoconazole 〉 itraconazole 〉 cyclosporin ~ troleandomycin 〉 erythromycin 〉 naringenin. For the inhibition of N-dealkylation, itraconazole ≥ ketoconazole 〉 cyclosporin ≥ naringenin ≥ erythromycin ≥ troleandomycin. Rifampin induction of CYP3A, a known effect of rifampin in vivo, was also reproduced in primary human hepatocytes. Induction of CYP3A4, measured as testosterone 6β-hydroxylation, was found to be dose-dependent, treatment duration-dependent, and reversible. The induction effect of rifampin was observed in hepatocytes isolated from all 7 human donors studied, with ages ranging from 1.7 to 78 years. To demonstrate that the rifampin-induction of testosterone 6β-hydroxylation could be generalized to other CYP3A4 substrates, we evaluated the metabolism of another known substrate of CYP3A4, lidocaine. Dose-dependent induction of lidocaine metabolism by rifampin is observed. Our results suggest that primary human hepatocytes may be a useful experimental system for preclinical evaluation of drug-drug interaction potential during drug development, and as a tool to evaluate the mechanism of clinically observed drug-drug interactions.

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URL: http://dx.doi.org/10.1023/A:1007451911843

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Rodent pharmacokinetic and anti-tumor efficacy studies with a series of synthetic inhibitors of matrix metalloproteinases (1997)

Santos, Orlando ; McDermott, Charles D ; Daniels, Richard G ; [et al.]

Springer

Clinical & experimental metastasis 15 (1997), S. 499-508

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ISSN: 1573-7276

Keywords: cancer ; Lewis lung carcinoma ; matrix metalloproteinases ; metastasis ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Matrix metalloproteinases are a family of zinc-containing proteases that degrade extracellular matrix and basement membranes. These enzymes are thought to play a role in processes essential for tumor growth, invasion, and metastasis. Here we report pharmacokinetic and anti-tumor efficacy studies with a series of structurally related inhibitors of these enzymes that were synthesized at Agouron Pharmaceuticals using protein structure based drug design. The compounds studied were AG3287, AG3293, AG3294, AG3296, AG3319, and AG3340. Rat oral bioavailability ranged from 15 to 68%. Despite similar profiles of enzyme inhibition across the family of enzymes, and similar pharmacokinetics following i.p. administration to mice, efficacy against the Lewis lung carcinoma murine model varied from tumor growth enhancement, to significant reductions in the size of primary tumors and the number of lung metastases. AG3340 was the most efficacious compound against the Lewis lung carcinoma model, resulting in the complete cessation of primary tumor growth throughout the experiment in 4/6 mice treated with daily i.p. injections at a dose of 50 mg/kg. This treatment inhibited the formation of lung metastases greater than 5 mm in diameter by 90%.

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URL: http://dx.doi.org/10.1023/A:1018418725453

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The Plasma Kinetics and Tissue Distribution of Enrofloxacin and its Metabolite Ciprofloxacin in the Muscovy Duck (1997)

Intorre, L. ; Mengozzi, G. ; Bertini, S. ; [et al.]

Springer

Veterinary research communications 21 (1997), S. 127-136

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ISSN: 1573-7446

Keywords: antibiotic ; ciprofloxacin ; distribution ; enrofloxacin ; Muscovy ducks ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Intorre, L., Mengozzi, G., Bertini, S., Bagliacca, M., Luchetti, E. and Soldani, G., 1997. The plasma kinetics and tissue distribution of enrofloxacin and its metabolite ciprofloxacin in the Muscovy duck. Veterinary Research Communications, 21 (2), 127-136 The disposition and tissue distribution of enrofloxacin and of its main metabolite ciprofloxacin were investigated in ducks after oral or intramuscular administration of a single dose of 10 mg/kg enrofloxacin. Plasma and tissue concentrations were determined by a HPLC method. The peak concentrations of enrofloxacin after intramuscular administration (1.67 µg/ml at 0.9 h) were higher than after an oral dose (0.99 µg/ml at 1.38 h). The relative bioavailability of enrofloxacin after administration directly into the crop was 68%, while the metabolic conversion of enrofloxacin to ciprofloxacin was quite low (〈10%) with both routes of administration. High tissue concentrations and high tissue:plasma concentration ratios were demonstrated for enrofloxacin and ciprofloxacin 24 h after treatment. It was concluded that a dose of 10 mg/kg per day provides serum and tissue concentrations sufficiently high to be effective in the control of many infectious diseases of ducks.

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URL: http://dx.doi.org/10.1023/A:1005773603905

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Chiou, Win L. ; Chung, Sang M. ; Robbie, Gabriel

Springer

Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 471-476

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ISSN: 1573-8744

Keywords: steady-state volume of distribution ; statistical moment analysis ; pharmacokinetics ; infusion study

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract A recent study by Heatherington and Rowland showing discrepancies in steady-state volume of distribution (Vss) estimation of two barbiturates between bolus and infusion studies in rat hindlimb preparations was reviewed. Their rationale is that increasing the duration of administration may increase the accessibility for tissue distribution and thus increase Vss for compounds showing slow tissue uptake. Such a dosing-duration-dependent distribution concept is, however, inconsistent with the principle in linear kinetics that the fate or disposition function of any drug molecules is independent of time of administration and presence of other molecules. When their well-designed bolus studies were reanalyzed by including extrapolated outflow data from the last sampling time to infinity, the Vss values for the two barbiturates were found to be very similar to those obtained by the infusion method. Our analysis seems to validate a theoretical concept that parameter estimation is independent of the duration of administration in linear kinetics. A potential complication of using the bolus method to study Vss is presented.

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URL: http://dx.doi.org/10.1023/A:1025745009925

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Mixed Effect Modeling of Sumatriptan Pharmacokinetics During Drug Development. I: Interspecies Allometric Scaling (1997)

Cosson, Valérie F. ; Fuseau, Eliane ; Efthymiopoulos, Constantin ; [et al.]

Springer

Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 149-167

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ISSN: 1573-8744

Keywords: sumatriptan ; interspecies allometric scaling ; brain weight ; metabolized drug ; pharmacokinetics ; mixed effect modeling ; NONMEM

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Allometric scaling is an empirical examination of the relationships between the pharmacokinetic parameters and size (usually body weight), but it can also involve brain weight for metabolized drug. Through all species, the protein binding of sumatriptan is similar (14-16%). and its metabolic pathway undergoes extensive oxidative deamination involving the monoamine oxidase A isoenzyme. These similarities across species suggested the possible relevance of an allometric analysis. Toxicokinetic data were collected from rats, pregnant rabbits, and dogs in animal pharmacokinetic studies where sumatriptan was administered intravenously to the animals at doses of 5 mg/kg. 0.25 mg/kg, and 1 mg, kg, respectively. Animal data were pooled and analyzed in one step using a mixed effect modeling (population) approach. The kinetic parameters predicted in any species were close to the observed values by species: 77 L/hr vs. 80 L/hr in man for total clearance, 137 L vs. 119 L for distribution volume at steady state. The value of the mixed effect modeling approach compared to the two-step method was demonstrated especially with the possibility of including covariates to describe the status of animal (e.g., pregnancy) in the model. Knowledge of the animal kinetics, dynamics, and metabolism of a drug contributes to optimal and expeditious development. Valuable information for the design of the first-dose-in-man study may emerge from more creative data analysis based on all the information collected during the preclinical and ongoing nonclinical evaluation of a new drug.

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URL: http://dx.doi.org/10.1023/A:1025728028890

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Quantitative Structure-Pharmacokinetics Relationships: I. Development of a Whole-Body Physiologically Based Model to Characterize Changes in Pharmacokinetics Across a Homologous Series of Barbiturates in the Rat (1997)

Blakey, Graham E. ; Nestorov, Ivan A. ; Arundel, Philip A. ; [et al.]

Springer

Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 277-312

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ISSN: 1573-8744

Keywords: pharmacokinetics ; physiologically based model ; homologous series ; barbiturates ; parameter optimization

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract As pan of an overall program to develop a framework for evaluating the contribution of structural and physicochemical properties to pharmacokinetics, the distribution kinetics of nine 5-n-alkyl-5-ethyl barbituric acids in arterial blood and 14 tissues (lung, liver, kidney, stomach, pancreas, spleen, gut, muscle, adipose, skin, bone, heart, brain, testes) was examined after iv bolus administration in rats. The barbituric acids studied form a true homologous series; therefore any differences in pharmacokinetics, noted between congeners, can be directly linked to the increase in lipophilicity, resulting from the addition of a methylene group. A whole-body physiologically based pharmacokinetic model has been developed, assuming most of the tissues to be well-stirred compartments. Brain and testes, in which distribution for the lower homologues was permeability rate-limited, were represented by two compartments. For each homologue, the model parameters have been optimized, using the tissue concentration–time data. The initial distribution processes in the system were very rapid, making it quite stiff, and essentially over before the first samples were taken. A progressively increasing redistribution from lean tissues into adipose on ascending the homologous series was observed, characterized by a tendency for a progressive decrease in the magnitude of the concentration–time profiles for some of the lean and well-perfused tissues, an increase in the adipose concentration–time profile, and an increase in the time to reach the maximum adipose concentration. A shift from permeability rate limitation to perfusion rate limitation of the distribution processes for brain and testes, as well as an increase in the intrinsic hepatic clearance and decrease in the renal clearance with the increase of lipophilicity of the homologues, were quantified. An increase in the total unbound volume of distribution on ascending the homologous series was also observed. Muscle was found to be the major drug depot at steady state, accounting for approximately 50% of the total unbound volume of distribution, regardless of the lipophilicity of the homologue; the unbound volume of distribution of adipose increases more than 10-fold with the increase of lipophilicity.

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URL: http://dx.doi.org/10.1023/A:1025771608474

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New Mathematical Implementation of Generalized Pharmacodynamic Models: Method and Clinical Evaluation (1997)

Stagni, Grazia ; Shepherd, Alexander M. M. ; Liu, Yanjuan ; [et al.]

Springer

Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 313-348

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ISSN: 1573-8744

Keywords: pharmacodynamics ; pharmacokinetics ; generalized models ; intraindividual variability ; verapamil ; norverapamil ; S-verapamil

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract A new method and experimental design are presented to unambiguously estimate the transduction function (Φ) and the conduction function (ψ) of the generalized pharmacodynamic model: E = Φ(ψ*r), when measured pharmacokinetic response r is (i) drug plasma concentration and (ii) drug input rate into the systemic circulation. Φ relates the observed pharmacologic effect E to the concentration at the effect site: ce = (ψ*r), ψ defines transfer of drug from plasma site to effect site or from input site to effect site, and * represents the convolution integral. The model functions ψ and Φ were expressed as cubic splines giving a very flexible description of those processes which is not biased by the structured assumptions of more conventional models, e.g., effect compartment models. The experimental design proposed addresses the problem of ambiguous identification of the model functions typical of these models; that is, there is more than one pair of very different functions describing the effect data collected after a single drug administration. We tested the hypothesis that the simultaneous fitting of at least two administrations allows the unambiguous identification of the model functions without the need for unlikely or cumbersome constraints. The performance of the mathematical implementation and the robustness of the methods with respect to measurement noise and possible failure of some assumptions, such as intraindividual variability, were tested by computer simulations. The method was then applied to the results of a clinical study of verapamil pharmacodynamics in 6 healthy subjects. Results of these studies demonstrated that the mathematical implementation does not introduce bias or artifact into the estimated functions and that the models and the proposed methods are suitable for application to clinical research. Two drug administrations were sufficient to unambiguously describe verapamil pharmacodynamics in the 6 human subjects studied.

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URL: http://dx.doi.org/10.1023/A:1025723725312

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A Tracer Interaction Method for Nonlinear Pharmacokinetics Analysis: Application to Evaluation of Nonlinear Elimination (1997)

Veng-Pedersen, P. ; Widness, J. A. ; Wang, J. ; [et al.]

Springer

Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 569-593

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ISSN: 1573-8744

Keywords: tracer method ; nonlinear kinetics ; Michaelis-Menten ; pharmacokinetics ; erythropoietin ; binding ; drug receptors ; receptor binding ; drug elimination ; modeling

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract A drug tracer is most commonly applied to get information about the pharmacokinetics (PK) of a drug that is not confounded by an endogenously produced drug or an unknown drug input. An equally important use of tracers that has not been fully recognized is their use in the study of nonlinear PK behavior. In the present study a system analysis is applied to examine the interaction between drug molecules characteristic and intrinsic to any nonlinear process which enables the nonlinearity to be identified and modeled using a drug tracer. The proposed Tracer Interaction Methodology (TIM) forms a general developmental framework for novel methods for examining nonlinear phenomena. Such methods are potentially much more sensitive and accurate than previous methods not exploiting the tracer principle. The methodology proposed is demonstrated in a simulation study and with real data in a specific implementation aimed at determining the Michaelis-Menten (MM) parameters of nonlinear drug elimination while accounting for drug distribution effects. The simulation study establishes that the TIM-based, MM parameter evaluation produces substantially more accurate parameter estimates than a nontracer (NT) conventional method. In test simulations the accuracy of the TIM was in many cases an order of magnitude better than the NT method without evidence of bias. The TIM-based, MM parameter estimation methodology proposed is ideally suitable for dynamic, non-steady-state conditions. Thus, it offers greater applicability and avoids the many problems specific to steady state evaluations previously proposed. TIM is demonstrated in an evaluation of the nonlinear elimination behavior of erythropoietin, a process that likely takes place via receptor-based endocytosis. Due to its high sensitivity, accuracy, and intrinsic nonlinearity the TIM may be suitable for in-vivo studies of receptor binding of the many biotechnology produced peptide drugs and endogenous compounds displaying receptor-mediated elimination.

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URL: http://dx.doi.org/10.1023/A:1025765330455

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Pharmacokinetic–Pharmacodynamic Modeling of Doxacurium: Effect of Input Rate (1997)

Zhu, Yali ; Audibert, Gérald ; Donati, François ; [et al.]

Springer

Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 23-37

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ISSN: 1573-8744

Keywords: pharmacokinetics ; pharmacodynamics ; neuromuscular blocking agents ; doxacurium ; input rate ; intravenous ; bolus ; infusion

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract One of the basic assumptions in pharmacokinetic–pharmacodynamic modeling (PK–PD) is that drug equilibration rate constant between plasma concentration and effect (Ke0 ) is not changed by input rate. To test this assumption in a clinical setting, a 25 μg/kg iv dose of doxacurium was administered either by bolus injection or 10-min infusion to 15 anesthetized patients. Neuromuscular function was monitored using train-of-four stimulation of the ulnar nerve. For the short infusion dose, arterial concentrations were measured at 1-min intervals during infusion and at frequent intervals thereafter. Following the iv bolus dose, the early PK profile of doxacurium was investigated by measuring doxacurium arterial concentrations every 10 sec during the first 2 min and at frequent intervals thereafter. PK–PD modeling was performed using nonparametric approach with and without including a finite receptor concentration (Rtot ) in the effect compartment. Kinetic parameters were unchanged. For the bolus and the infusion, Ke0 values were 0.053±0.006 and 0.056±0.009 min −1 , respectively. Using the Rtot model, corresponding Ke0 values were 0.148±0.016 and 0.150±0.024, respectively. The relatively faster Ke0 obtained with the Rtot model is compatible with the high potency of doxacurium. Our results show that PK–PD parameters derived with either a bolus or an infusion mode of administration are equally reliable.

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URL: http://dx.doi.org/10.1023/A:1025715626164

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Mathematical Formalism for the Properties of Four Basic Models of Indirect Pharmacodynamic Responses (1997)

Krzyzanski, Wojciech ; Jusko, William J.

Springer

Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 107-123

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ISSN: 1573-8744

Keywords: pharmacodynamic responses ; pharmacokinetics ; differential equations ; drug ; indirect response models

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Four basic models for characterizing indirect pharmacodynamic responses were proposed previously and applied using differential equations. These models consider inhibition or stimulation by drug of the production or loss of mediators or response variables. This report develops partially integrated solutions for these models which allow more detailed examination of the roles of model parameters and pharmacokinetic functions in affecting the time course of drug effects. Because of the nonlinear Hill function, the solutions are represented by means of definite integrals containing kinetic and dynamic functions. These solutions allow a qualitative examination, using calculus, of how response is controlled by Dose. IC50 or SC50, Imax or Smax, and kout for drugs exhibiting monotonic or biphasic disposition. Characteristics of the response curves that were identified include shape, maximum or minimum, and changes with the above parameters and time. These relationships, together with simulation studies, provide a fundamental basis for understanding the temporal aspects of the basic indirect response models.

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URL: http://dx.doi.org/10.1023/A:1025723927981

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Bioavailability Assessment from Pharmacologic Data: Method and Clinical Evaluation (1997)

Stagni, Grazia ; Shepherd, Alexander M. M. ; Liu, Yanjuan ; [et al.]

Springer

Journal of pharmacokinetics and pharmacodynamics 25 (1997), S. 349-362

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ISSN: 1573-8744

Keywords: bioavailability ; pharmacologic data ; pharmacodynamics ; pharmacokinetics ; computer simulation ; verapamil

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract A novel method is described for assessing drug bioavailability from pharmacologic data. The method is based upon a generalized model for the relationship between the observed effect (E) and the input rate (f): E = Φ(ceδ * f), where * denotes convolution, ceδ is effect site unit impulse response (“amount” of drug at the effect site resulting from the instantaneous input of a unit amount of drug) and Φ is transduction function (relates “amount” of drug at the effect site to E). The functions Φ and ceδ are expressed as cubic splines for maximum versatility. Pharmacologic data collected after the administration of two different doses by iv infusion are analyzed simultaneously to estimate the function parameters. This experimental design addresses the fact that Φ and ceδ cannot be uniquely estimated from the results of a single dose experiment. The unknown f from a test treatment is then estimated by applying an implicit deconvolution method to the pharmacologic data collected during that treatment. The method was tested with simulated data. The method and the model were further evaluated by application to a clinical study of verapamil (V) pharmacodynamics in 6 healthy volunteers. Simulations showed that the method is accurate and precise in the presence of a high degree of measurement error, but large intrasubject variability in the model functions can result in biased estimates of the amount absorbed. The method produced reasonably accurate estimates of the V input rate and systemic availability (F) in the 6 human volunteers though there was a trend towards underestimation (estimated total F%=93.6±14 vs. the true F% of 100).

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URL: http://dx.doi.org/10.1023/A:1025775809382

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Prospective Use of Population Pharmacokinetics/ Pharmacodynamics in the Development of Cisatracurium (1997)

Schmith, Virginia D. ; Fiedler-Kelly, Jill ; Phillips, Luann ; [et al.]

Springer

Pharmaceutical research 14 (1997), S. 91-97

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ISSN: 1573-904X

Keywords: pharmacokinetics ; pharmacodynamic modeling ; NONMEM ; model validation ; cisatracurium

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. The population PK/PD approach was prospectively used to determine the PK/PD of cisatracurium in various subgroups of healthy surgical patients. Methods. Plasma concentration (Cp) and neuromuscular block data from 241 patients in 8 prospectively-designed Phase I−III trials were pooled and analyzed using NONMEM. The analyses included limited Cp-time data randomly collected from 186 patients in efficacy/safety studies and full Cp-time data from 55 patients in pharmacokinetic studies. The effects of covariates on the PK/PD parameters of cisatracurium were evaluated. The time course of neuromuscular block was predicted for various patient subgroups. Results. The population PK/PD model for cisatracurium revealed that anesthesia type, gender, age, creatinine clearance, and presence of obesity were associated with statistically significant (p 〈 0.01) effects on the PK/PD parameters of cisatracurium. These covariates were not associated with any clinically significant changes in the predicted recovery profile of cisatracurium. Slight differences in onset were predicted in patients with renal impairment and patients receiving inhalation anesthesia. Based on the validation procedure, the model appears to be accurate and precise. Conclusions. The prospective incorporation of a population PK/PD strategy into the clinical development of cisatracurium generated information which influenced product labeling and reduced the number of studies needed during development.

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URL: http://dx.doi.org/10.1023/A:1012015719694

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Mirtazapine Pharmacokinetics with Two Dosage Regimens and Two Pharmaceutical Formulations (1997)

Timmer, Cees J. ; Paanakker, Jan E. ; Vrijmoed-de Vries, Maria

Springer

Pharmaceutical research 14 (1997), S. 98-102

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ISSN: 1573-904X

Keywords: Remeron ; mirtazapine ; Org 3770 ; antidepressant ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. To compare, in a clinical study of a special design, the pharmacokinetic profile of mirtazapine in 20 young healthy male volunteers on two treatment regimens with homothetic oral tablets at steady state: NOCTE (1 × 30 mg at 21.00 h) and BID (15 mg at 21.00 h and 15 mg at 09.00 h). Methods. Pharmacokinetic parameters were calculated from mirtazapine plasma levels assayed by gas chromatography with nitrogen-sensitive detection. A special analysis of variance allowed interesting interactions to be distinguished. Results. The steady state was reached after 4 and 6 days for NOCTE and BID respectively; the difference was presumably due to intersubject variability. In accordance with pharmacokinetic theory, the peak-to-trough ratio at steady state was significantly lower (twofold) for BID than for NOCTE. Within BID, a small difference (approx. 10%) was found in the extent of absorption between evening and morning administration. Although statistically significant, this difference meets strict bioequivalence requirements. The regimens NOCTE and BID were found to be bioequivalent for the steady-state area-under-the-curve-curve and the peak time. Bioequivalence testing for the peak level was not meaningful due to the difference in dosing regimens. The observed elimination half-lives of 19.7 ± 3.0 h and 20.8 ± 2.7 h (n = 20) for NOCTE and BID, respectively are in agreement with previous results. Conclusions. Differences (if any) were found to meet strict bioequivalence requirements and were so small that they are of no clinical consequence.

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URL: http://dx.doi.org/10.1023/A:1012067703764

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Validation of a Decision Support System for Use in Drug Development: Pharmacokinetic Data (1997)

Guzy, Serge ; Hunt, Anthony

Springer

Pharmaceutical research 14 (1997), S. 1287-1297

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ISSN: 1573-904X

Keywords: pharmacometrics ; pharmacokinetics ; simulate ; predict ; validate ; clinical trial ; population ; decision support ; informatics ; bootstrap ; clinical outcomes ; algorithm

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. Single dose pharmacokinetic data from several individuals can be used to predict the fraction of the population that is expected to be within a therapeutic range. Without having some measure of its reliability, however, that prediction is only likely to marginally influence critical drug development decision making. The system (Forecaster) described generates an approximate prediction interval that contains the original prediction and where, for example, the probability is approximately 85% that a similar prediction from a new set of data will also be within the range. The goal is to validate that the system functions as designed. Methods. The strategy requires having a Surrogate Population (SP), which is a large number (≥1500) of hypothetical individuals each represented by set of model parameter values having unique attributes. The SP is generated so that a sample taken from it will give data that is statistically indistinguishable from the available experimental data. The automated method for building the SP is described. Results. Validation studies using 300 independent samples document that for this example the SP can be used to make useful predictions, and that the approximate prediction interval functions as designed. Conclusions. For the boundary conditions and assumptions specified, the Forecaster can make valid predictions of pharmacokinetic-based population targets that without a SP would not be possible. Finally, the approximate prediction interval does provide a useful measure of prediction reliability.

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URL: http://dx.doi.org/10.1023/A:1012191831815

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Characterization of Poly(glycolide-co-D,L-lactide)/Poly(D,L-lactide) Microspheres for Controlled Release of GM-CSF (1997)

Pettit, Dean K. ; Lawter, J. Ronald ; Huang, W. James ; [et al.]

Springer

Pharmaceutical research 14 (1997), S. 1422-1430

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ISSN: 1573-904X

Keywords: poly(glycolide-co-D,L-lactide) ; poly(D,L-lactide) ; granulocyte-macrophage colony-stimulating factor (GM-CSF) ; biodegradable microspheres ; pharmacokinetics ; resorbable polymer

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. This study describes the preparation and characterization of a controlled release formulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) encapsulated in poly(glycolide-co-D,L-lactide) (PLGA) and poly(D,L-lactide) (PLA) microspheres. Methods. GM-CSF was encapsulated in PLGA/PLA microspheres by a novel silicone oil based phase separation process. Several different blends of PLGA and low molecular weight PLA were used to prepare the microspheres. The microspheres and the encapsulated GM-CSF were extensively characterized both in vitroand in vivo. Results. Steady release of GM-CSF was achieved over a period of about one week without significant 'burst' of protein from the microspheres. Analysis of microsphere degradation kinetics by gel permeation chromatography (GPC) indicated that low molecular weight PLA enhanced the degradation of the PLGA and thereby affected release kinetics. GM-CSF released from the microspheres was found to be biologically active and physically intact by bioassay and chromato-graphic analysis. Analysis of serum from mice receiving huGM-CSF indicated that the GM-CSF was biologically active and that a concentration of greater than 10 ng/mL was maintained for a period lasting at least nine days. MuGM-CSF was not detected followingin vivo administration of muGM-CSF microspheres. The tissues of mice receiving muGM-CSF microspheres were characterized by infiltration of neutrophils, and macrophages which were in significant excess of those found in mice administered with placebo controls (i.e. microspheres without GM-CSF). Conclusions. This study demonstrates the influence of formulation parameters on the encapsulation of GM-CSF in PLGA/PLA microspheres and its controlled release in biologically active form. The intense local tissue reaction in mice to muGM-CSF microspheres demonstrates the importance of the mode of delivery on the pharmacologic activity of GM-CSF.

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URL: http://dx.doi.org/10.1023/A:1012176823155

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The Design and Validation of a Novel Intravenous Microdialysis Probe: Application to Fluconazole Pharmacokinetics in the Freely-Moving Rat Model (1997)

Yang, Hua ; Wang, Qin ; Elmquist, William F.

Springer

Pharmaceutical research 14 (1997), S. 1455-1460

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ISSN: 1573-904X

Keywords: intravenous microdialysis ; blood sampling ; fluconazole ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. The purpose of this study was to design and validate a concentric, flexible intravenous microdialysis probe to determine drug concentrations in blood from the inferior vena cava of a freely-moving animal model. Methods. An intravenous microdialysis probe was constructed using fused-silica tubing and an acrylonitrile/sodium methallyl sulfonate copolymer hollow fiber. The probe was tested in vitro for the recovery of fluconazole and UK-54,373, a fluconazole analog used for probe calibration by retrodialysis. Subsequent in vivo validation was done in rats (n = 7) that had a microdialysis probe inserted into the inferior vena cava via the femoral vein, and the femoral artery was cannulated for simultaneous blood sampling. Comparisons of fluconazole pharmacokinetic parameters resulting from the two sampling methods were performed at 2 and 10 days after probe implantation. Results. There were no statistical differences between the microdialysis sampling and conventional blood sampling methods for the T1/2, Cl, Vdss, and dose-normalized AUC by paired t-test (p 〉 0.05) for repeated dosing at day 2 and day 10 after probe placement. The probe recovery, as determined by retrodialysis, significantly decreased over the ten day period. This finding indicates the necessity for frequent recovery determinations during a long-term blood microdialysis experiment. Conclusions. These results show that microdialysis sampling in the inferior vena cava using this unique and robust probe design provides an accurate method of determining blood pharmacokinetics in the freely-moving rat for extended experimental periods. The probe design allows for a simple surgical placement into the inferior vena cava which results in a more stable animal preparation for long-term sampling and repeated-measures experimental designs.

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URL: http://dx.doi.org/10.1023/A:1012137209042

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The Pharmacokinetics of Topotecan and Its Carboxylate Form Following Separate Intravenous Administration to the Dog (1997)

Davies, Brian E. ; Minthorn, Elisabeth A. ; Dennis, Michael J. ; [et al.]

Springer

Pharmaceutical research 14 (1997), S. 1461-1465

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ISSN: 1573-904X

Keywords: topotecan ; pharmacokinetics ; topoisomerase I inhibitor ; reversible metabolism

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. To determine the relationship between topotecan and its ring opened hydrolysis product (SK&F 105992) following intravenous administration of the two agents separately, and to determine the bio-availability of topotecan in female beagle dogs. Methods. The pharmacokinetics of topotecan and SK&F 105992 were determined following separate administration as 30 minute intravenous infusions in a cross-over design. Topotecan was also administered orally to the same dogs. Results. When administered intravenously to dogs, SK&F 105992 underwent interconversion to topotecan. Plasma concentrations of both topotecan and SK&F 105992 appeared to decline multi-exponentially following IV infusion of either compound. A 2-compartment model was found to adequately characterize the data. Conclusions. The clearance of topotecan by other routes proceeded at a faster rate than its interconversion to SK&F 105992, whereas the clearance of SK&F 105992 by other routes was slower than the rate of its interconversion to topotecan. Any SK&F 105992 formed in the GI tract did not appear to be well absorbed following oral administration of topotecan to dogs. The steady-state volume of distribution for topotecan was approximately 8- to 9-fold greater than that for SK&F 105992 in the dog. After intravenous administration of topotecan, the amount of topotecan in the dog was much greater than that of the carboxylate, even though their respective plasma concentrations were similar. The bioavailability of topotecan, calculated from oral topotecan data or from SK&F 105992 data, was approximately 50%.

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URL: http://dx.doi.org/10.1023/A:1012189225880

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Pharmacokinetic and Pharmacological Profiles of Free and Liposomal Recombinant Human Erythropoietin After Intravenous and Subcutaneous Administrations in Rats (1997)

Moriya, Hidetaka ; Maitani, Yoshie ; Shimoda, Naoto ; [et al.]

Springer

Pharmaceutical research 14 (1997), S. 1621-1628

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ISSN: 1573-904X

Keywords: recombinant human erythropoietin ; liposome ; intravenous administration ; subcutaneous administration ; pharmacokinetics ; pharmacological effect

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. Recombinant human erythropoietin (Epo) is used frequently through intravenous (i.v.) and subcutaneous (s.c.) administration for the clinical treatment of the last stage of renal anemia. We encapsulated Epo in liposomes to develop an alternative administration route. The purpose of our study was to evaluate the pharmacokinetics and the pharmacological effects of liposomal Epo in comparison with the Epo after i.v. and s.c. administration to rats. Methods. Epo was encapsulated in liposomes composed of dipalmitoylphosphatidylcholine (DPPC) and soybean-derived sterol mixture (SS) prepared by the reversed-phase evaporation vesicle method. After filtration through a 0.1 μm polycarbonate membrane, liposomes were gel filtered (Epo/liposomes). Results. Epo/liposomes showed higher pharmacological activity than Epo/liposomes before gel filtration after i.v. administration to rats. Non-encapsulated Epo lost its activity, whereas encapsulated Epo in liposomes retained it. The pharmacological effects of Epo/liposomes were greater than those of Epo after i.v. administration. Epo/liposomes afforded 3−9 times higher AUC, lower clearance and lower steady-state volume of distribution than Epo after both i.v. and s.c. administrations. Epo/liposomes had an improved pharmacokinetic profile compared with Epo. S.c. administration of Epo/liposomes at 7 h may penetrate primarily (40% of dose) through the blood as a liposome and partly (7% of dose) in lymph. Conclusions. Epo/liposomes may reduce the frequency of injections required for a certain reticulocyte effect in comparison to Epo. The lower clearance of Epo/liposomes may increase the plasma concentrations of Epo, which increases the efficacy.

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URL: http://dx.doi.org/10.1023/A:1012142704924

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Distribution Kinetics of Diazepam, Lidocaine and Antipyrine in the Isolated Perfused Rat Hindlimb (1997)

Weiss, Michael ; Koester, Armin ; Wu, Zhen Yu ; [et al.]

Springer

Pharmaceutical research 14 (1997), S. 1640-1643

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ISSN: 1573-904X

Keywords: pharmacokinetics ; indicator dilution ; permeability ; dispersion ; model

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

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URL: http://dx.doi.org/10.1023/A:1012198922671

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The Pharmacokinetics and Electroencephalogram Response of Remifentanil Alone and in Combination with Esmolol in the Rat (1997)

Haidar, Sam H. ; Moreton, J. Edward ; Liang, Zhongming ; [et al.]

Springer

Pharmaceutical research 14 (1997), S. 1817-1823

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ISSN: 1573-904X

Keywords: remifentanil ; esmolol ; pharmacokinetics ; pharmacodynamics ; electroencephalogram

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. The goal of this study was to determine if the co-administration of esmolol (ES), a short acting cardioselective β-blocker, significantly alters the pharmacokinetics and/or pharmacodynamics of remifentanil (REMI), an ultra short-acting opioid, in the rat. Methods. Sprague-Dawley rats (N = 8, Wt. = 325 ± 15g) were surgically implanted with stainless steel cerebrocortical EEG electrodes three days before the study. Each rat was dosed with REMI (15 μg/ kg/min), and REMI & ES (15 μg/kg/min and 600 μg/kg/min) for 21 minutes in a random crossover design. Six serial blood samples were collected over 25 minutes into test-tubes containing 0.5ml acetonitrile. Blood samples were extracted with methylene chloride and analyzed by a validated GC-MS assay. EEG was captured and subjected to power spectral analysis (0.1−50 Hz) for spectral edge (97%). Results. No significant differences (p 〈 0.05) were found in clearance (REMI = 287 + 73 ml/min/leg vs. REMI & ES = 289 ± 148 ml/ min kg) or Vd (REMI = 286 ± 49 ml/kg vs REMI & ES = 248 + 40 ml/kg). A linked sigmoid Emax PK-PD model was used and the pharmacodynamic parameters were not statistically different. Mean Emax and EC50 after REMI were 18.0 ± 6.0 Hz and 32 ± 12 ng/ml; and after REMI + ES were 19 + 4.8 Hz and 26 + 8.6 ng/ml. Conclusions. At the doses tested, there is no pharmacokinetic or pharmacodynamic interaction between remifentanil and esmolol in the rat.

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URL: http://dx.doi.org/10.1023/A:1012156502624

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Drug Equilibration Across the Blood—Brain Barrier-Pharmacokinetic Considerations Based on the Microdialysis Method (1997)

Hammarlund-Udenaes, Margareta ; Paalzow, Lennart K. ; de Lange, Elizabeth C. M.

Springer

Pharmaceutical research 14 (1997), S. 128-134

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ISSN: 1573-904X

Keywords: microdialysis ; blood-brain barrier transport ; pharmacokinetics ; drug equilibration

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. The purpose of the study was to investigate the influence of different rates of transport into and out of the brain, including passive and active transport, on unbound brain concentrations and profile in relation to the blood concentration profile. Special emphasis is put on hydrophilic drugs. Methods. Simulations were performed with a model including one body compartment and one brain compartment, with linear or saturable transport into and out of the brain. Comparisons were made with experimental results from microdialysis (MD) studies. Results. Three features were evident when combining the MD results: 1) equilibration across the blood-brain barrier (BBB) is rapid, 2) half-life is similar in brain and blood for most drugs, and 3) unbound brain concentrations seldom reach the level of unbound blood concentrations. A low concentration ratio brain:blood is not mainly caused by a low influx, but rather by different influx and efflux clearances. Active transport out of the brain can explain the results, but also active transport into the brain under certain conditions. A small volume of distribution in brain vs. that in the rest of the body contributes to a rapid equilibration and similar half-lives. Conclusions. Assumptions of slow equilibration of hydrophilic drugs and similar unbound concentrations across the BBB at steady state are contradicted. The results are more in line with recent findings on the presence of P-glycoprotein and other transport mechanisms at the BBB. Non-passive transport across the BBB seems to be the case for almost all drugs studies with MD so far.

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URL: http://dx.doi.org/10.1023/A:1012080106490

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The Use of Human Hepatocytes to Select Compounds Based on Their Expected Hepatic Extraction Ratios in Humans (1997)

Lavé, Th. ; Dupin, S. ; Schmitt, C. ; [et al.]

Springer

Pharmaceutical research 14 (1997), S. 152-155

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ISSN: 1573-904X

Keywords: human hepatocytes ; extraction ratio ; pharmacokinetics ; clearance ; in vitro models

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. The present investigation retrospectively evaluates the use of human hepatocytes to classify compounds into low, intermediate or high hepatic extraction ratio in man. Methods. A simple approach was used to correlate the in vivo hepatic extraction ratio of a number of compounds in man (literature and in-house data) with the corresponding in vitro clearance which was determined in human hepatocytes. The present approach assumes that, for compounds eliminated mainly through liver metabolism, intrinsic clearance is the major determinant for their in vivo hepatic extraction ratio and subsequently their bioavailability in man. The test compounds were selected to represent a broad range of extraction ratios and a variety of metabolic pathways. Results. The present data show that in vitro clearances in human hepatocytes are predictive for the hepatic extraction ratios in vivo in man. Most of the test compounds (n = 19) were successfully classified based upon human hepatocyte data into low, intermediate or high hepatic extraction compounds, i.e. compounds with potential for high, intermediate or low bioavailabilities in humans. Conclusions. The present approach, validated so far with 19 test compounds, appears to be a valuable tool to screen for compounds with respect to liver first-pass metabolism at an early phase of drug discovery.

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URL: http://dx.doi.org/10.1023/A:1012036324237

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Pharmacokinetics and Antiepileptic Activity of Valproyl Hydroxamic Acid Derivatives (1997)

Levi, Micha ; Yagen, Boris ; Bialer, Meir

Springer

Pharmaceutical research 14 (1997), S. 213-217

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ISSN: 1573-904X

Keywords: valproic acid ; valproyl hydroxamic acid derivatives ; pharmacokinetics ; antiepileptic activity ; structural requirements

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. To explore the utilization of seven novel hydroxamic acid derivatives of valproic acid (VPA) as new antiepileptics. Methods. The study was carried out by investigating the pharmacokinetics of two active compounds in dogs and pharmacodynamics (anti-convulsant activity and neurotoxicity) of valproyl hydroxamic acid and six of its derivatives. Results. Three valproyl hydroxamic acid derivatives: valproyl hydroxamic acid—VPA-HA, N-(l-hydroxyethyl)-valpromide—HEV and N-methoxy valpromide, showed better anticonvulsant activity than VPA at the maximal electroshock (MES) test. The remaining four compounds, O-valproyl-VPA-HA, N-valproyl-O-valproyl-VPA-HA, N-(l-methoxyethyl) valpromide and N-( 1,2-dihydroxylpropyl)-valpromide were found to be inactive. Therefore, only the pharmacokinetics of the active compounds VPA-HA and HEV was studied. Conclusions. In contrast to valpromide (VPD) which is biotransformed to VPA, VPA-HA and HEV were found to be stable in vivo to the biotransformation of the amide to its corresponding acid. VPA-HA and HEV showed improved anticonvulsant activity over VPA because of their greater intrinsic activity and not due to better pharmacokinetic characteristics. This paper discusses the structural requirements for active anticonvulsant valproyl hydroxamic acid derivatives.

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URL: http://dx.doi.org/10.1023/A:1012009012850

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The Role of Liver and Kidney on the Pharmacokinetics of a Recombinant Amino Terminal Fragment of Bactericidal/Permeability-Increasing Protein in Rats (1997)

Bauer, Robert J. ; Der, Kenneth ; Ottah-Ihejeto, Nneka ; [et al.]

Springer

Pharmaceutical research 14 (1997), S. 224-229

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ISSN: 1573-904X

Keywords: bactericidal/permeability-increasing protein ; pharmacokinetics ; liver ; kidney ; heparin

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. The pharmacokinetics of rBPI23, a recombinant amino terminal fragment of bactericidal/permeability-increasing protein that binds to and neutralizes endotoxin, was investigated. Methods. rBPI23 was administered to rats at doses 0.01−10 mg/kg and plasma rBPI23 levels were measured by ELISA. rBPI23 was also administered to bilaterally nephrectomized rats. In addition, rBPI23 was administered intra-hepatically via the pyloric vein to determine the first-pass effect by the liver. rBPI23 concentrations were also simultaneously measured in the right atrium and aorta to determine the removal of rBPI23 by the lungs. Results. The concentration-time profile of rBPI23 was described by a 3-compartmental model with parallel first order and Michaelis-Menten (saturable) elimination. The clearance of rBPI23 was not altered by bilateral nephrectomy. Clearance of intra-hepatically administered rBPI23 was 4.5 fold lower than intra-femorally administered rBPI23. The concentration difference of rBPI23 between aortic and right atrial blood was no greater than 11%. Clearance of rBPI23 in rats could be reduced up to 10 fold by co-administration of heparin. Uptake by liver of intra-hepatically administered rBPI23 was prevented by co-administration of heparin. Conclusions. rBPI23 is not significantly cleared by the kidneys, and no more than 11% of the rBPI23 was removed by the lungs with each pass. The liver could remove 78% of the rBPI23 from the hepatic circulation. Studies with heparin suggest rBPI23 is cleared by binding to heparan sulfate sites in the liver.

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URL: http://dx.doi.org/10.1023/A:1012013113759

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Application of Microdialysis in Pharmacokinetic Studies (1997)

Elmquist, William F. ; Sawchuk, Ronald J.

Springer

Pharmaceutical research 14 (1997), S. 267-288

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ISSN: 1573-904X

Keywords: microdialysis sampling ; pharmacokinetics ; drug distribution ; probe recovery ; blood-brain barrier ; extracellular fluid

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract The objective of this review is to survey the recent literature regarding the various applications of microdialysis in pharmacokinetics. Microdialysis is a relatively new technique for sampling tissue extracellular fluid that is gaining popularity in pharmacokinetic and pharmacodynamic studies, both in experimental animals and humans. The first part of this review discusses various aspects of the technique with regard to its use in pharmacokinetic studies, such as: quantitation of the microdialysis probe relative recovery, interfacing the sampling technique with analytical instrumentation, and consideration of repeated procedures using the microdialysis probe. The remainder of the review is devoted to a survey of the recent literature concerning pharmacokinetic studies that apply the microdialysis sampling technique. While the majority of the pharmacokinetic studies that have utilized microdialysis have been done in the central nervous system, a growing number of applications are being found in a variety of peripheral tissue types, e.g. skin, muscle, adipose, eye, lung, liver, and blood, and these are considered as well. Given the rising interest in this technique, and the ongoing attempts to adapt it to pharmacokinetic studies, it is clear that microdialysis sampling will have an important place in studying drug disposition and metabolism.

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URL: http://dx.doi.org/10.1023/A:1012081501464

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Pharmacokinetics and Pharmacodynamics of an Investigational Antipsychotic Agent, CI-1007, in Rats and Monkeys (1997)

Feng, Meihua Rose ; Corbin, Ann E. ; Wang, Yanfeng ; [et al.]

Springer

Pharmaceutical research 14 (1997), S. 329-336

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ISSN: 1573-904X

Keywords: antipsychotic ; pharmacokinetics ; pharmacodynamics ; active metabolite ; rat ; monkey

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. To study the pharmacokinetics (PK) and pharmacodynamics (PD) of an investigational antipsychotic agent, CI-1007, in rats and monkeys. Methods. CI-1007 and a pharmacologically active metabolite, PD 147693 (Ml), were evaluated in animal antipsychotic tests (inhibition of dopamine neuron firing and spontaneous locomotor activity in rats, and inhibition of continuous avoidance in monkeys). Plasma concentrations of CI-1007 and Ml were determined using validated HPLC assays. Log-linear and link models were used for PK/PD analysis. Results. CI-1007 and Ml have shown similar effects on dopamine neuron firing (2.5 mg/kg i.p.), and produced dose-related effects on spontaneous locomotor activity in rats (0.3−30 mg/kg, p.o.) and on continuous avoidance in monkeys (0.6−1.2 mg/kg p.o.). After pharmacologically active CI-1007 doses, mean plasma CI-1007 Cmax increased from 19 to 200 ng/ml in Sprague-Dawley rats at doses of 3−30 mg/ kg, and from 8.1 to 34 ng/ml in squirrel monkeys at doses of 0.6−1.2 mg/kg, but corresponding plasma M1 Cmax values were near or below the limit of quantitation (5 ng/ml). CI-1007 EC50 was 31.1 ng/ml in rats, calculated from a log-linear regression. In monkeys, CI-1007 ECe50, γ, and Keo at 0.6 and 1.2 mg/kg were 4.8 and 4.5 ng/ml, 1.9 and 2.0, and 0.47 and 0.48 hr−1, respectively, calculated by the link model. Conclusions. CI-1007 has shown dose-related pharmacokinetics and pharmacodynamics in rats and monkeys. Although Ml produces anti-psychotic-like effects similar to CI-1007, the contribution of Ml to the activity of the parent drug may not be significant in rats and monkeys as based on plasma levels. CI-1007 plasma concentration correlates log-linearly with inhibition effect from the rat locomotor study. The counter-clockwise hysteresis relationship of CI-1007 plasma concentration and inhibition effect from the monkey avoidance test was described by a link model, and the resulting Ce (concentration in effect compartment) versus effect profile exhibits a sigmoidal curve.

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URL: http://dx.doi.org/10.1023/A:1012050121937

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Studies on the Mechanism of Absorption of Depot Neuroleptics: Fluphenazine Decanoate in Sesame oil (1997)

Luo, Jiang-Ping ; Hubbard, John W. ; Midha, Kamal K.

Springer

Pharmaceutical research 14 (1997), S. 1079-1084

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ISSN: 1573-904X

Keywords: fluphenazine decanoate ; prodrug ; fluphenazine ; pharmacokinetics ; single dose

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. The purpose of the present study was to investigate the pharmacokinetic characteristics of fluphenazine (FLU) and its decanoate (FLU-D) after intravenous and intramuscular administration to dogs. Methods. A group of four beagle dogs was used in all intravenous and intramuscular experiments, with washout periods of no less than three months between doses. Results. After intravenous FLU-D, the pharmacokinetics of the prodrug (mean ± SD) were as follows: Clearance (CL) 42.9 ± 6.3 L/h; terminal half-life (t1/2) 3.5 ± 0.8 h; volume of distribution (Vd) 216 ± 61 L. The fractional availability of FLU was 1.0 ± 0.2. After intravenous FLU, the volume of distribution of FLU (51 ± 17.8 L) was some 4 fold less than that of the prodrug. Simulations (Stella II) suggested that the rate limiting step was slow formation of FLU from the prodrug in the tissue compartment. After intramuscular FLU-D in sesame oil, the apparent t1/2 of FLU was 9.7 ± 2.0 days whereas after intramuscular FLU base in sesame oil, the apparent t1/2 was only 7.7 ± 3.4 h showing that the absorption of FLU itself from the intramuscular site and proximal lymph nodes is relatively rapid. Conclusions. The rate limiting step after intramuscular FLU-D appeared to be the slow partitioning of the prodrug out of the sesame oil at the injection site and in proximal lymph nodes.

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URL: http://dx.doi.org/10.1023/A:1012165731390

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Development of tricalcium phosphate/amylopectin paste combined with recombinant human transforming growth factor beta 1 as a bone defect filler (1997)

Ongpipattanakul, Boonsri ; Nguyen, Tue ; Zioncheck, Thomas F. ; [et al.]

Hoboken, NJ : Wiley-Blackwell

Journal of Biomedical Materials Research 36 (1997), S. 295-305

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ISSN: 0021-9304

Keywords: bone defect filler ; transforming growth factor-β1 ; release kinetics ; in vivo efficacy ; pharmacokinetics ; Chemistry ; Polymer and Materials Science

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Medicine , Technology

Notes: Tricalcium phosphate (TCP) was combined with amylopectin to form a deliverable carrier paste for recombinant human transforming growth factor β1 (rhTGF-β1) intended for bone repair applications. Approximately 80% of rhTGF-β1 was released from the carrier within 24 h following in vitro incubation in serum. Full biological activity was maintained, suggesting the growth factor was stable in this formulation before and after in vitro release. In vivo efficacy also was assessed, in comparison to a sham control group and a placebo-treated group, using a rabbit unilateral segmental defect model (1 cm). Radiographs of defect sites taken at scheduled intervals and the mechanical testing of treated limbs at 56 days demonstrated a higher incidence of radiographic bone union, in concert with a stronger torque strength, in the rhTGF-β1-treated group compared to the placebo group. The short duration of the study and the fact that the model used was not a critical defect may account for the lack of superiority of the rhTGF-β1-treated group over the healing of the sham control. The in vivo pharmacokinetics of the growth factor evaluated in the same rabbit model suggested that rhTGF-β1 persisted intact at the defect site for more than 21 days. Gamma imaging and radioactivity recovery at defects administered to [131I]- and [125I]-labeled rhTGF-β1, respectively, estimated the half-life of rhTGF-β1 eliminated from the applied site to be 4-6 days. The present report substantiates the potential of rhTGF-β1 and its carrier for treatment of bone defects. © 1997 John Wiley & Sons, Inc. J Biomed Mater Res., 36, 295-305, 1997.

Additional Material: 5 Ill.

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