Pharmacokinetics and pharmacodynamics of a novel orally active angiotensin converting enzyme inhibitor (HOE 498) in healthy subjects

Witte, Peter Uwe; Irmisch, R; Hajdú, P; Metzger, H.

doi:10.1007/bf00556895

Cited by 65 publications

(24 citation statements)

References 10 publications

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“…The biphasic pharmacokinetic profile of cilazaprilat observed in this group of hypertensive patients is qualitatively similar to that observed with other non-thiol containing ACE inhibitors (Ulm et al, 1982;Witte et al, 1984;Lees & Reid, 1987). The profile is consistent with high affinity saturable binding of cilazprilat to plasma ACE.…”

Section: Discussionsupporting

confidence: 81%

The pharmacokinetics and angiotensin converting enzyme inhibition dynamics of cilazapril in essential hypertension.

Modesti

Elliott

Reid

et al. 1989

Brit J Clinical Pharma

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1 In a double-blind, placebo controlled, crossover study 12 patients with essential hypertension received single doses of 5, 10 and 20 mg of cilazapril. 2 Peak plasma levels of cilazaprilat and the 24 h areas under curve were directly proportional to dose. 3 The elimination half-life during the first 8 h was about 1.7 h. 4 From 24 h onwards there was a prolonged terminal elimination phase with a half-life of about 40 h, and strict dose proportionality of plasma concentrations was not maintained. 5 The pharmacokinetics of cilazaprilat and the pharmacodynamics of plasma ACE inhibition were well described by a one compartment model with saturable binding to ACE. 6 The coefficients of the model which related to plasma ACE and its interaction with cilazaprilat were in good agreement with model independent observations. 7 The values for kinetic and dynamic parameters in hypertensive patients were comparable with those reported for healthy volunteers.

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Section: Discussionsupporting

confidence: 81%

The pharmacokinetics and angiotensin converting enzyme inhibition dynamics of cilazapril in essential hypertension.

Modesti

Elliott

Reid

et al. 1989

Brit J Clinical Pharma

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“…This study has confirmed the rapid absorption of ramipril and its conversion to the active metabolite ramiprilat after oral administration (Becker et al 1984;Witte et al 1984). The peak concentration of ramiprilat in plasma appeared about 2 hours following oral administration of ramipril.…”

Section: Discussionsupporting

confidence: 65%

Pharmacokinetics and pharmacodynamics of ramipril and piretanide administered alone and in combination

Ruf

Gera²,

Luus

et al. 1994

Eur J Clin Pharmacol

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The pharmacokinetics and pharmacodynamics of single oral doses of 5 mg ramipril and 6 mg piretanide administered separately and in combination were determined in a single blind, randomised, 3-period cross-over study in 24 healthy male volunteers. The peak plasma concentrations of ramipril and ramiprilat increased slightly (from 11.9 to 14.8 ng/ml, and from 6.39 to 8.96 ng/ml, respectively) as did the area under the plasma concentration-time curve of ramipril (0-4 h) and ramiprilat (0-24 h) (from 15.8 to 19.8 ng.ml-1.h, and from 63.4 to 74.6 ng.ml-1.h, respectively). The urinary excretion of ramiprilat also rose (from 6.82 to 7.73% of dose) following simultaneous treatment with piretanide. These effects were probably due to reduced first-pass metabolism of ramipril/ramiprilat to inactive metabolites. The blood pressure lowering effect, the time course of inhibition of ACE activity in plasma and the concentration-response relationship for the inhibition of plasma ACE activity were not affected by piretanide. The peak plasma concentration of piretanide was somewhat reduced (from 285 to 244 ng/ml) following simultaneous treatment with ramipril. No other pharmacokinetic parameter was affected. Piretanide increased urine flow, and sodium, chloride and potassium excretion, especially during the first 2 hours following administration. These pharmacodynamic parameters were not affected by ramipril. Thus, simultaneous administration of single oral doses of ramipril and piretanide caused modest changes in the peak and average plasma concentrations of both drugs, which did not lead to detectable alterations in the pharmacodynamic parameters measured in healthy volunteers.

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“…An interval of at least 2 weeks separated study days. The long wash-out period was chosen because ramiprilat can still be detected more than a week after administration of a single dose of ramipril [20].…”

Section: Medication and Dosagementioning

confidence: 99%

Pharmacokinetics, pharmacodynamics and bioavailability of the ACE inhibitor ramipril

Griensven

Schoemaker

Cohen

et al. 1995

Eur J Clin Pharmacol

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The pharmacokinetics and pharmacodynamics of the prodrug ramipril and its active ACE-inhibiting metabolite ramiprilat were investigated in an open, randomised, three-way cross-over study in 12 healthy male volunteers. Subjects received 2.5 mg ramipril orally, 2.5 mg ramipril intravenously and 2.5 mg ramiprilat intravenously. The absolute bioavailability as judged by ramipril plasma AUC was 15%, by ramiprilat plasma AUC, 44%. Ramiprilat formation from intravenous ramipril was 53% and from oral ramipril 28%. Urinary recovery of oral ramipril was 23%, i.v. ramipril 49%, and i.v. ramiprilat 68% of the given dose. Maximum ACE inhibition was highest (100%) after i.v. ramiprilat; it was 99% after i.v. ramipril and 84% following oral ramipril. ACE inhibition over 24 h was highest after i.v. ramipril, 2% less with i.v. ramiprilat and 34% less with oral ramipril. Ramiprilat renal clearance was concentration dependent. The biological availability of ramipril can best be judged by ramiprilat AUC, urinary recovery of ramipril and metabolites, or ACE inhibition over 24 h. It is concluded that the bioavailability of oral ramipril seems to be in the range of 44-66%.

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Pharmacokinetics and pharmacodynamics of a novel orally active angiotensin converting enzyme inhibitor (HOE 498) in healthy subjects

Cited by 65 publications

References 10 publications

The pharmacokinetics and angiotensin converting enzyme inhibition dynamics of cilazapril in essential hypertension.

The pharmacokinetics and angiotensin converting enzyme inhibition dynamics of cilazapril in essential hypertension.

Pharmacokinetics and pharmacodynamics of ramipril and piretanide administered alone and in combination

Pharmacokinetics, pharmacodynamics and bioavailability of the ACE inhibitor ramipril

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