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  • 1
    Electronic Resource
    Electronic Resource
    Kinetics of canrenone after single and multiple doses of spironolactone (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 255-262 
    Details
    ISSN: 1432-1041
    Keywords: spironolactone ; canrenone ; fluorimetry ; high performance liquid chromatography ; linear kinetics ; saturation kinetics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In Study I 20 normal volunteers received a single oral dose of spironolactone 100 mg. In Study II a further 20 normal volunteers were given first spironolactone 100 mg b.i.d. and subsequently spironolactone 100 mg once a day for a further 4 days. In Study III 5 normal subjects were given a single dose of spironolactone 500 mg. The concentration of canrenone in serum was determined both by fluorimetry and HPLC for 0–48 h in Study I, 120–168 h in Study II and 0–36 h in Study III. The total AUCs after the single 100 mg dose did not differ from the AUCs within the dosing interval during steady state. The half-lives of the terminal log-linear phases were almost identical (14.99±0.80 h and 15.69±0,80 h) when determined by fluorimetry, and were sligthly, but significantly (p〈0.01), longer when determined by HPLC — 20.14±1.62 and 18.71±1.04. The mean ratio of the specific AUC determined by HPLC and the fluorimetrically determined AUC was 0.3 after the single 100 mg dose. It did not differ from the corresponding value during steady state (0.34). In contrast, the ratio after the single 500 mg dose was approximately 50% higher. Fluorimetrically determined AUCs after 100 and 500 mg doses did not show dose-proportionality in contrast to the HPLC-determined AUCs. It was concluded that Canrenone contributes much less to the conventional fluorimetric determination than was previously assumed. It may not provide more than 1/10 and 1/4 of the antimineralocorticoid activity of spironolactone after single dose and multiple doses, respectively. Whereas linear kinetics apply after single and multiple 100 mg doses of spironolactone, after 500 mg saturation kinetics must be assumed with respect to metabolism. Thus, in bioavailability studies high doses of spironolactone should be avoided. For such studies the fluorimetric assay seems to be the appropriate bioanalytical method in spite of its lower specificity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00608404
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  • 2
    Electronic Resource
    Electronic Resource
    Disposition pharmacokinetics of bezafibrate in man (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 31-38 
    Details
    ISSN: 1432-1041
    Keywords: bezafibrate ; hyperlipoproteinemia ; bioavailability ; pharmacokinetics ; GC-MS
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition kinetics of bezafibrate, a newly developed drug of great lipid-lowering potency, were investigated in normal male subjects. Five male volunteers received14C-labelled bezafibrate orally in solution, and a further 10 were given the same dose (300 mg) of un-labelled drug as tablets. The concentration of bezafibrate in serum and urine from the latter was determined by GC, and in the former total radioactivity in serum, urine and feces was followed for 48 h, and urinary excretion products were analysed by TLC and GC-MS. Rapid absorption from the gastrointestinal tract led to peak serum levels 30 min and 2 h after administration of solution and tablets, respectively. Since approximately 95% of the administered14C-bezafibrate was excreted in urine within 48 h, and almost all the remainder was detected in feces, absorption can be regarded as complete after administration in solution. The relative optimal bioavailability from the tablets was also complete, since in both cases approximately 50% of the administered dose was detected as unchanged bezafibrate in urine within 24 h by GC in the tablet study, and by TLC in the solution study. Of the decomposition products, more than 20% of the dose was present as glucuronides and the remainder consisted of several more polar compounds, one of which was identified as a hydroxyderivative of bezafibrate. Since the apparent halflife of bezafibrate in serum was 2.1 h, this new drug possesses favourable pharmacokinetic features: rapid and complete absorption, even from tablets, combined with a conveniently short half-life, and clearance which is half renal (56 ml/min) and half metabolic (43 ml/min), giving a total clearance of 99 ml/min.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00644963
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  • 3
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of ramipril in hypertensive patients with renal insufficiency (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 249-256 
    Details
    ISSN: 1432-1041
    Keywords: ramipril ; renal insufficiency ; hypertension ; pharmacokinetics ; ramiprilat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In an open trial, the pharmacokinetics of ramipril and its active metabolite ramiprilat were studied in 25 hypertensive patients with various degrees of renal insufficiency given 5 mg ramipril p.o. for 14 days. Ramipril was rapidly absorbed and reached a peak concentration after 1–2 h. Cmax was greater in patients with severe renal insufficiency, which might indicate a reduced renal elimination rate, although, the rapid decline of the concentration-time curve for ramipril was almost independent of renal function. The mean initial apparent half-lives on Days 1 and 12, respectively, were 2.8 and 3.4 h (Group I: creatinine clearance 5–15 ml/min), 1.8 and 2.3 h (Group II: creatinine clearance 15–40 ml/min), and 1.9 and 1.9 h (Group III: creatinine clearance 40–80 ml/min). No accumulation was observed after multiple dosing. In contrast, the kinetics of its active acid metabolite ramiprilat was significantly influenced by renal function. The mean times to the peak plasma concentration were 5.7 h in Group I, 4.4 h in Group II and 3.8 h in Group III. The initial decline in plasma ramiprilat was dependent upon renal function; the mean initial apparent half-lives (Days 1 and 12, respectively) were 16.0 and 14.8 h (Group I), 10.1 and 9.5 h (Group II) and 10.6 and 8.0 h (Group III). Mean trough concentrations and absolute accumulation also increased with worsening renal function, and the renal clearance of ramiprilat was significantly correlated with the creatinine clearance. The subsequent long terminal phase at low plasma ramiprilat concentrations represented slow dissociation of the ACE-inhibitor complex. The study indicates that in patients with severe renal insufficiency (creatinine clearance below 30 ml/min) smaller doses of ramipril are required than in patients with normal or borderline renal function.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00679779
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  • 4
    Electronic Resource
    Electronic Resource
    Ursachen der Potenzierung der hypoglykämischen Wirkung von Sulfonylharnstoff-Derivaten durch Medikamente (1971)
    Springer
    European journal of clinical pharmacology 4 (1971), S. 32-37 
    Details
    ISSN: 1432-1041
    Keywords: Glibenclamide ; pharmacokinetics ; metabolism ; potentiation of hypoglycemic action ; phenylbutazone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Description / Table of Contents: Summary Metabolically healthy subjects were given an intravenous injection of 1,13 mg14C-labelled glibenclamide (HB 419). The plasma level, renal elimination of the radioactivity and metabolism of the substance were investigated. Two minutes after administration the HB 419 is virtually present only in the blood and at the end of the distribution period mostly in the extracellular space. 53% of the radioactivity is excreted via the kidneys in the form of metabolites. If glibenclamide is administrated in the same way to the same subjects after pretreatment with phenylbutazone there are no differences in the course of the plasma levels or the rate of elimination from the blood. There is, however, a significant difference in the excretion of the radioactivity in the urine. In the presence of phenylbutazone significantly less HB 419 metabolite is excreted renally. In view of the known alternative route of elimination it is suggested that the amount not excreted in the urine is in compensation eliminated via the bile. There was no difference in the metabolism of glibenclamide between the control and phenylbutazone treated groups. The potentiation by phenylbutazone of HB 419 action, and probably also that of other antidiabetic sulphonylureas, must therefore be due predominantly to other causes (Communication III).
    Notes: Zusammenfassung Stoffwechselgesunde Versuchspersonen erhielten14C-markiertes Glibenclamid in einer Dosis von 1.13 mg/Vpn i.v. gespritzt. Plasmaspiegelverläufe, renale Elimination der Radioaktivität und die Metabolisierung der Substanz wurden untersucht. Zwei Minuten nach der Applikation ist HB 419 praktisch nur im Blutund nach Abschluß der Verteilung weitgehend im Extracellulärraum vorhanden. 53% der Radioaktivität werden über die Nieren in Form von Metaboliten ausgeschieden. Wird den gleichen Probanden nach Prämedikation mit Phenylbutazon Glibenclamid in gleicher Weise verabfolgt, ergibt sich kein Unterschied hinsichtlich der Plasmaspiegelverläufe und der Eliminationsgeschwindigkeit aus dem Blut. Ein signifikanter Unterschied besteht jedoch in der Ausscheidung der Radioaktivität in den Harn (26.3%). In Gegenwart von Phenylbutazon wird ein signifikant geringerer Anteil von HB 419-Metaboliten renal eliminiert. Aufgrund des bekannten zweiten Ausscheidungsweges wird vermutet, daß der fehlende Anteil kompensatorisch über die Galle eliminiert wird. Die Metabolisierung von Glibenclamid weist keine Differenzen zwischen Phenylbutazon-und Kontroll-Gruppe auf. Die Wirkungspotenzierung von HB 419 — wahrscheinlich auch diejenige anderer antidiabetisch wirksamer Sulfonylharnstoffe — durch Phenylbutazon dürfte demnach überweigend andere Ursachen haben. (Mitteilung III).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00568896
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  • 5
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of ranitidine in renal impairment (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 229-234 
    Details
    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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  • 6
    Electronic Resource
    Electronic Resource
    β-Methyl-digoxin (1973)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 279 (1973), S. 211-226 
    Details
    ISSN: 1432-1912
    Keywords: Cardiac Glycosides ; Brain ; Behaviour ; Distribution ; Protein Binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Rats and mice were injected with 3H-labelled β-methyldigoxin, digoxin or digitoxin i.p. Four hours later, the concentrations of radioactivity were measured in the plasma and in skeletal muscle or in the brain. Protein binding in the plasma was determined and the concentration of radioactivity in the plasma water was calculated. By dividing the injected dose or the concentration in the tissue by that in the plasma water, distribution coefficients (DCs) were calculated for the whole body, skeletal muscle and brain. Some extra-cardiac effects of the three glycosides were quantified and the concentrations that may be expected in plasma water, skeletal muscle and brain after the administration of equiactive doses were calculated. 1. The DC of the injected dose was lower for β-methyl-digoxin than for digoxin and digitoxin. This difference cannot be explained by a slow elimination of β-methyl-digoxin suggesting that it has a low distribution volume in these species. 2. In rats, the DC between skeletal muscle and plasma water decreased in the order digitoxin 〉 digoxin ≫ β-methyl-digoxin. 3. In mice and rats, the DC between brain and plasma water decreased in the order digitoxin ≫ β-methyl-digoxin 〉 digoxin. 4. Protein binding decreased in the order digitoxin ≫ digoxin 〉 β-methyldigoxin. 5. In rats, the doses producing an equal increase in potassium excretion decreased in the order digitoxin 〉 digoxin 〉 β-methyl-digoxin. On the other hand, the concentrations of radioactivity in the plasma water correlated with these doses decreased in the order β-methyl-digoxin 〉 digitoxin ≫ digoxin. There was no significant difference between the intracellular concentrations of digoxin and β-methyl-digoxin in skeletal muscle. 6. In mice, there was no clear correlation between inhibition of spontaneous motility or righting reflexes on the rotating rod and the concentrations of radioactivity in the plasma water or in the brain. β-Methyl-digoxin is moee lipophilic than digoxin but it penetrates less into skeletal muscle. It is as lipophilic as digitoxin, but it penetrates less into the brain of rats and mice. This shows that penetration of the cell membrane by cardiac glycosides does not solely depend on lipid solubility.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00500601
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  • 7
    Electronic Resource
    Electronic Resource
    β-methyl-digoxin (1978)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 302 (1978), S. 87-90 
    Details
    ISSN: 1432-1912
    Keywords: Cats ; Cardiac glycosides ; Brain ; Distribution ; Side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The tissue/plasma ratio of β-methyl-digoxin for cardiac muscle in cats was about the same 24 h after a single dose of 30 μg/kg as after a loading dose of 30 μg/kg followed by 3 maintenance doses of 7.5 μg/kg at 24 h intervals. The ratio for the brain increased 2-fold during that time. After the i.v. injection of a toxic loading dose of 70 μg/kg β-methyl-digoxin or digoxin, maintenance doses of as little as 15 μg/kg at 48 h intervals sufficed to maintain the minimum plasma glycoside concentrations determined by RIA at about 3 ng/ml. There was no difference in the plasma concentrations or in the severity of intoxication produced by both glycosides. Cats vomited within 3 h after i.v. injection of 100 μg/kg β-methyl-digoxin, whereas a loading dose of 30 μg/kg followed by 3 injections of 7.5 μg/kg at 24 h intervals were well tolerated. The concentration of radioactivity in the brain 3 h after 100 μg/kg was less than 24 h after the last injection of 7.5 μg/kg in the experiments with repeated dosage. Cerebral side-effects such as vomiting, loss of appetite and weight were better correlated with the glycoside concentrations in the plasma than with those in the brain.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00586602
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