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  • 1
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of CPT-11 in rhesus monkeys (1997)
    Springer
    Cancer chemotherapy and pharmacology 41 (1997), S. 103-108 
    Details
    ISSN: 1432-0843
    Keywords: Key words CPT-11 ; Pharmacokinetics ; Monkey
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: To examine the pharmacokinetic relationships between humans and monkeys, we studied the disposition of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), in rhesus monkeys. Methods: CPT-11 was administered to a total of six monkeys at doses of 3, 7, 15 and 25 mg/kg by intravenous infusion for 10 min and plasma concentrations and pharmacokinetic parameters of CPT-11 determined. Results: Maximum plasma concentrations at 25 mg/kg reached around 10 000 ng/ml, and dropped to 500 ng/ml in 8 h. Plasma concentrations of SN-38 remained between 2 and 10 ng/ml. Mean values of systemic clearance, mean residence time and distribution volume at steady state, the major pharmacokinetic parameters for CPT-11, were 13.3 (ml/min per kg), 192 (min) and 2553 (ml/kg), respectively. The initial plasma concentration ratio of lactone to total CPT-11, 76%, declined to about 20% within 75 min, and the final ratio was about 40% at 8 h; the initial ratio of SN-38 was 72%, dropped to 34% within 70 min and finally recovered to 55% at 8 h. Conclusion: Comparison with human data revealed that systemic clearances of CPT-11 and the maximum AUC of SN-38 were not as different between humans and monkeys as between humans and mice, but the metabolic conversion of CPT-11 into SN-38 in monkeys was significantly lower than in humans.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050715
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  • 2
    Electronic Resource
    Electronic Resource
    Effects of Intestinal CYP3A4 and P-Glycoprotein on Oral Drug Absorption—Theoretical Approach (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 225-231 
    Details
    ISSN: 1573-904X
    Keywords: oral absorption ; CYP3A4 ; P-glycoprotein ; diffusion model ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate the effects of gut metabolism and efflux on drug absorption by simulation studies using a pharmacokinetic model involving diffusion in epithelial cells. Methods. A pharmacokinetic model for drug absorption was constructed including metabolism by CYP3A4 inside the epithelial cells, P-gp-mediated efflux into the lumen, intracellular diffusion from the luminal side to the basal side, and subsequent permeation through the basal membrane. Partial differential equations were solved to yield an equation for the fraction absorbed from gut to the blood. Effects of inhibition of CYP3A4 and/or P-gp on the fraction absorbed were simulated for a hypothetical substrate for both CYP3A4 and P-gp. Results. The fraction absorbed after oral administration was shown to increase following inhibition of P-gp. This increase was more marked when the efflux clearance of the drug was greater than the sum of the metabolic and absorption clearances and when the intracellular diffusion constant was small. Furthermore, it was demonstrated that the fraction absorbed was synergistically elevated by simultaneous inhibition of both CYP3A4 and P-gp. Conclusions. The analysis using our present diffusion model is expected to allow the prediction of in vivo intestinal drug absorption and related drug interactions from in vitro studies using human intestinal microsomes, gut epithelial cells, CYP3A4-expressed Caco-2 cells, etc.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018872207437
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  • 3
    Electronic Resource
    Electronic Resource
    Quantitative Prediction of In Vivo Drug-Drug Interactions from In Vitro Data Based on Physiological Pharmacokinetics: Use of Maximum Unbound Concentration of Inhibitor at the Inlet to the Liver (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 336-343 
    Details
    ISSN: 1573-904X
    Keywords: drug interaction ; prediction ; physiologically-based pharmacokinetics ; tolbutamide ; sulfaphenazole
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To assess the degree to which the maximum unboundconcentration of inhibitor at the inlet to the liver (Iinlet,u,max), used in theprediction of drug-drug interactions, overestimates the unboundconcentration in the liver. Methods. The estimated value of Iinlet,u,max was compared with theunbound concentrations in systemic blood, liver, and inlet to the liver,obtained in a simulation study based on a physiological flow model.As an example, a tolbutamide/sulfaphenazole interaction was predictedtaking the plasma concentration profile of the inhibitor intoconsideration. Results. The value of Iinlet,u,max differed from the concentration in eachcompartment, depending on the intrinsic metabolic clearance in theliver, first-order absorption rate constant, non-hepatia clearance andliver-to-blood concentration ratio (Kp) of the inhibitor. The AUC oftolbutamide was predicted to increase 4-fold when co-administeredwith sulfaphenazole, which agreed well with in vivo observations andwas comparable with the predictions based on a fixed value of Iinlet,u,max.The blood concentration of tolbutamide was predicted to increase whenit was co-administered with as little as 1/100 of the clinical doseof sulfaphenazole. Conclusions. Although Iinlet,u,max overestimated the unboundconcentration in the liver, the tolbutamide/sulfaphenazole interaction couldbe successfully predicted by using a fixed value of Iinlet,u,max, indicatingthat the unbound concentration of sulfaphenazole in the liver after itsclinical dose is by far larger than the concentration to inhibitCYP2C9-mediated metabolism and that care should be taken when it isco-administered with drugs that are substrates of CYP2C9.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007509324428
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  • 4
    Electronic Resource
    Electronic Resource
    Prediction of In Vivo Interaction Between Triazolam and Erythromycin Based on In Vitro Studies Using Human Liver Microsomes and Recombinant Human CYP3A4 (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 419-426 
    Details
    ISSN: 1573-904X
    Keywords: drug interaction ; mechanism-based inhibition ; triazolam ; erythromycin ; physiologically-based pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To quantitatively predict the in vivo interaction betweentriazolam and erythromycin, which involves mechanism-basedinhibition of CYP3A4, from in vitro studies using human liver microsomes(HLM) and recombinant human CYP3A4 (REC). Methods. HLM or REC was preincubated with erythromycin in thepresence of NADPH and then triazolam was added. α- and 4-hydroxy(OH) triazolam were quantified after a 3 min incubation and the kineticparameters for enzyme inactivation (kinact and K′ app) were obtained.Drug-drug interaction in vivo was predicted based on aphysiologically-based pharmacokinetic (PBPK) model, using triazolam anderythromycin pharmacokinetic parameters obtained from the literature and kineticparameters for the enzyme inactivation obtained in the in vitro studies. Results. Whichever enzyme was used, triazolam metabolism was notinhibited without preincubation, even if the erythromycin concentrationwas increased. The degree of inhibition depended on preincubationtime and erythromycin concentration. The values obtained for kinactand K′ app were 0.062 min−1 and 15.9 μM (α-OH, HLM), 0.055 min−1and 17.4 μM (4-OH, HLM), 0.173 min−1 and 19.1 μM (α-OH, REC),and 0.097 min−1 and 18.9 μM (4-OH, REC). Based on the kineticparameters obtained using HLM and REC, the AUCpo of triazolamwas predicted to increase 2.0- and 2.6-fold, respectively, followingoral administration of erythromycin (333 mg t.i.d. for 3 days), whichagreed well with the reported data. Conclusions. In vivo interaction between triazolam and erythromycinwas successfully predicted from in vitro data based on a PBPK modelinvolving a mechanism-based inhibition of CYP3A4.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007572803027
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  • 5
    Electronic Resource
    Electronic Resource
    Classification of benzodiazepine hypnotics in humans based on receptor occupancy theory (1993)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 21 (1993), S. 31-41 
    Details
    ISSN: 1573-8744
    Keywords: benzodiazepine ; hypnotics ; receptor occupancy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Benzodiazepine (BZP) hypnotics are now classified into four groups according to their plasma elimination rates: ultrashort-, short-, intermediate-, and long-acting drugs. Since the specific binding affinities for the BZP receptor vary widely among the BZPs and their active metabolites, it may be more reasonable to correlate their pharmacological activities with the BZP receptor occupancy rather than with their plasma concentrations. The time courses of total plasma concentrations of BZPs and their active metabolites after a single oral administration were obtained from the literature, and their unbound concentrations (Cu)were calculated from the reported values of their plasma unbound fractions. The data of the receptor binding affinities of the BZPs, reported as dissociation constants (Kd)determined by in vitrobinding experiments, were also obtained from the literature. Using these values, the time courses of receptor occupancies [Cu/(Kd + Cu) ×100%] were calculated for the various BZPs. A mutual competitive inhibition was considered in the case of the drugs that had active metabolites. Although plasma total and unbound concentration time profiles of the BZPs showed a wide variation, similar patterns were obtained for the time courses of the receptor occupancy among the BZPs in each group, indicating that the BZP hypnotics can be classified more conveniently based on receptor occupancy theory.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061774
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  • 6
    Electronic Resource
    Electronic Resource
    Risk assessment of adverse pulmonary effects induced by adrenaline β-receptor antagonists and rational drug dosage regimen based on receptor occupancy (1995)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 23 (1995), S. 463-478 
    Details
    ISSN: 1573-8744
    Keywords: β-blocking agent ; cardiovascular selectivity ; receptor occupancy ; ternary complex model ; adverse pulmonary effect ; dosage regimen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract To clarify the β-1 selectivity of β-adrenergic receptor blocking agents (β-blocking agents) after typical oral doses, the relationships between the effects on exercise heart rate or FEV1 and β-1 or β-2 receptor occupancies (Φ 1 ,Φ 2 ) of seven β-blocking agents, acebutolol, atenolol, metoprolol, oxprenolol, timolol, propranolol, and pindolol were analyzed retrospectively. Nonlinear relationships between the pharmacologic effect andΦ 1 and between the pulmonary adverse effect andΦ 2 were obtained. Based on these findings, a new index of cardiovascular selectivity is proposed, given by the ratio of β-1 receptor occupancy to β-2 receptor occupancy (Φ 1 /Φ 2 ). Using this new index, there was a little difference in β-1 selectivity between acebutolol and pindolol (3.1:1.0), in contrast to a marked difference in β-1 selectivity (320:1) as a conventional index between these two drugs. This finding indicates that even β-1 selective drugs must be administered carefully to patients with pulmonary disease. Furthermore, the relationship between the pharmacologic or pulmonary effects andΦ 1 orΦ 2 has been analyzed quantitatively with a ternary complex model and used to develop rational dosage regimens for β-1 selective β-blocking agents, such as atenolol, to obtain the desired pharmacologic effects with minimum adverse pulmonary effects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02353469
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  • 7
    Electronic Resource
    Electronic Resource
    Prediction of the therapeutic dose for β-stimulants based on preclinical data: Application of oral dosage forms and aerosols to asthmatic patients (1993)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 21 (1993), S. 133-144 
    Details
    ISSN: 1573-8744
    Keywords: β-stimulant ; bronchial asthma ; therapeutic dose ; dosing rate prediction ; β-agonists
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The therapeutic doses of β-stimulants in the treatment of bronchial asthma show wide variation among the drugs. In the present study, we tried to construct a system for prediction of the optimum clinical dose of β-stimulants as oral dosage forms and aerosols using the data from preclinical pharmacological studies and pharmacokinetic data in humans. Values of EC50 (drug concentration that gives the half-maximum bronchodilator effect) in the in vitro studies based on isolated trachea of guinea pigs were collected from the literature. The ratios of the EC50 value of each drug to that of isoproterenol were used as the indicator of in vitro pharmacological activity. There were significant correlations between the EC50 ratios and the oral dose or the maximum plasma concentration after single oral administration, but the correlation coefficients were relatively small (r〈.9). On the other hand, a linear log-log relationship was observed between the EC50 ratio and the maximum plasma unbound concentration (Cumax) (slope=0.907, r=.955, p〈0.001). In the case of aerosols, a good correlation was observed between the EC50 ratio and the dose (slope=0.770, r=.900, p〈0.01). The predicted concentration of β-stimulants in the lung after aerosol administration tended to be higher than the Cumax after oral administration, suggesting the contribution of nonspecific binding in the lung tissue. These findings indicate the possibility of predicting the appropriate dose of β-stimulants based on the preclinical pharmacological data and the pharmacokinetic data in humans.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059766
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  • 8
    Electronic Resource
    Electronic Resource
    Pharmacokinetic Analysis of Benzodiazepine Receptor Binding of [123I]Iomazenil in Human Brain (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 999-1003 
    Details
    ISSN: 1573-904X
    Keywords: iomazenil ; SPECT ; benzodiazepine receptor ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of this study is to evaluate the central benzodiazepine (BZP) receptor binding of iomazenil (IMZ) by pharmacokinetic analysis and to establish a methodology for the diagnosis of CNS disorders with abnormalities in BZP receptor binding. Methods. BZP receptor binding of IMZ was analyzed kinetically using plasma concentration-time profiles and dynamic single photon emission computed tomography (SPECT) data obtained after the intravenous administration of IMZ to patients with neuropsychiatric diseases. The analysis was based on a 3-compartmental model including the processes of both blood-brain barrier (BBB) transport and BZP receptor binding. Results. Hydrolized metabolite of IMZ was detected in plasma, indicating the need for separation by HPLC. The BBB influx clearance and the receptor binding potential of IMZ in the medial temporal region was reduced in the epileptic patient. Conclusions. Our findings suggest the possibility of detecting the epileptic focus by using our method.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1012188909100
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