Pharmacokinetics of a Single Dose of Ramipril in Patients with Renal Dysfunction

Shionoiri, Hiroshi; Miyakawa, Tomomi; Yasuda, Gen; Ishikawa, Yoshihiro; Umemura, Satoshi; Miyajima, Eiji; Kaneko, Yoshihiro

doi:10.1097/00005344-198706107-00031

Cited by 7 publications

(2 citation statements)

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“…The only site of ramiprilat removal is renal clearance. This is consistent with the observation of a 3 to 4 fold decrease in ramiprilat clearance in renal failure patients with a 3 to 4 fold reduction in creatinine clearance [ 69 , 71 ].…”

Section: Discussionsupporting

confidence: 92%

Human physiologically based pharmacokinetic model for ACE inhibitors: ramipril and ramiprilat

Levitt

Schoemaker

2006

BMC Clin Pharmacol

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BackgroundThe angiotensin-converting enzyme (ACE) inhibitors have complicated and poorly characterized pharmacokinetics. There are two binding sites per ACE (high affinity "C", lower affinity "N") that have sub-nanomolar affinities and dissociation rates of hours. Most inhibitors are given orally in a prodrug form that is systemically converted to the active form. This paper describes the first human physiologically based pharmacokinetic (PBPK) model of this drug class.MethodsThe model was applied to the experimental data of van Griensven et. al for the pharmacokinetics of ramiprilat and its prodrug ramipril. It describes the time course of the inhibition of the N and C ACE sites in plasma and the different tissues. The model includes: 1) two independent ACE binding sites; 2) non-equilibrium time dependent binding; 3) liver and kidney ramipril intracellular uptake, conversion to ramiprilat and extrusion from the cell; 4) intestinal ramipril absorption. The experimental in vitro ramiprilat/ACE binding kinetics at 4°C and 300 mM NaCl were assumed for most of the PBPK calculations. The model was incorporated into the freely distributed PBPK program PKQuest.ResultsThe PBPK model provides an accurate description of the individual variation of the plasma ramipril and ramiprilat and the ramiprilat renal clearance following IV ramiprilat and IV and oral ramipril. Summary of model features: Less than 2% of total body ACE is in plasma; 35% of the oral dose is absorbed; 75% of the ramipril metabolism is hepatic and 25% of this is converted to systemic ramiprilat; 100% of renal ramipril metabolism is converted to systemic ramiprilat. The inhibition was long lasting, with 80% of the C site and 33% of the N site inhibited 24 hours following a 2.5 mg oral ramipril dose. The plasma ACE inhibition determined by the standard assay is significantly less than the true in vivo inhibition because of assay dilution.ConclusionIf the in vitro plasma binding kinetics of the ACE inhibitor for the two binding sites are known, a unique PBPK model description of the Griensven et. al. experimental data can be obtained.

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Section: Discussionsupporting

confidence: 92%

Human physiologically based pharmacokinetic model for ACE inhibitors: ramipril and ramiprilat

Levitt

Schoemaker

2006

BMC Clin Pharmacol

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“…In detail, Mendes et al reported an average ramipril/ramiprilat concentration of 13/9.8 ng/mL at 0.5/3.4 h after a single oral dose of 5 mg [ 2 ]. Based on Shionori et al a single oral dose of 10 mg ramipril yielded an average ramipril/ramiprilat concentration of 18/4.7 ng/mL at 1.2/3.2 h [ 3 ]. Meyer et al revealed that a dose of 20 mg ramipril resulted in an average ramipril/ramiprilat concentration of 52/34 ng/mL at 0.7/2.1 h [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

The analysis of ramipril/ramiprilat concentration in human serum with liquid chromatography-tandem mass spectrometry – interpretation of high concentrations for the purposes of forensic toxicology

Dziadosz

Rosenberger

Klintschar

et al. 2023

Forensic Sci Med Pathol

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Ramipril is a popular angiotensin-converting enzyme inhibitor applied in the treatment of hypertension. Its therapeutic effect is oriented on the concentration of the active metabolite ramiprilat. The information about toxic drug levels is missing in the literature. Therefore, the aim of this work was an indication of possible toxic ranges based on the analysis of real samples with high ramiprilat concentrations. For these purposes, an appropriate analytical LC–MS/MS method was developed and validated according to forensic guidelines and applied in the routine. Most real samples targeted for ramipril/ramiprilat were associated with the typical therapeutic drug range of 1–40 ng/mL described in the literature. However, higher drug levels with ramiprilat concentrations above 100 ng/mL could also be observed infrequently in cases of driving under the influence of drugs or attempted suicides. To the best of the author’s knowledge, this is the first time antemortem ramipril and ramiprilat concentrations associated with driving under the influence of drugs and suicide attempts were discussed from a forensic point of view. The collected data enabled an indication of the ramiprilat toxic concentration range from about 600 ng/mL to at least 3500 ng/mL. The toxic concentration range discussed can be applied in the forensic practice as a reference for future cases.

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The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients

Gehr

Sica

Grasela

et al. 1993

Eur J Clin Pharmacol

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The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium (a new angiotensin-converting enzyme (ACE) inhibitor), were investigated in six haemodialysis patients. Intravenous 14C-fosinoprilat (7.5 mg), oral 14C-fosinopril sodium (10 mg) and oral fosinopril sodium (10 mg) were administered in an open-label, randomized study. Mean maximum concentration (Cmax), clearance (CL), volume of distribution at steady-state (Vss), mean residence time (MRTiv), and t1/2 values after IV administration of 14C-fosinoprilat were 2,042 micrograms.ml-1, 11.3 ml.min-1, 11.0 l, 16.3 h and 28.3 h, respectively. Following oral administration of 14C-fosinopril, mean Cmax, time to maximum plasma concentration (tmax), and fosinoprilat bioavailability values were 197 ng.ml-1, 5.2 h and 29.2%. Para-hydroxy fosinoprilat and fosinoprilat glucuronide comprised approximately 15% and 2% of radioactivity recovered in faeces. Four hours of haemodialysis only cleared approximately 1.5% of the administered dose. The maximum effect (Emax) model was fitted to the percentage inhibition of serum ACE activity vs. fosinoprilat concentration data in three patients. Emax ranged from 95.3 to 102.5%, and IC50 (the fosinoprilat concentration required to produce 50% of Emax) ranged from 2.6 to 4.2 ng.ml-1. Pharmacokinetic variables of the patients were similar to those in patients with moderate to severe renal dysfunction. Dosage modifications or supplemental dosing following dialysis are unnecessary.

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Pharmacokinetics of a Single Dose of Ramipril in Patients with Renal Dysfunction

Cited by 7 publications

References 0 publications

Human physiologically based pharmacokinetic model for ACE inhibitors: ramipril and ramiprilat

Human physiologically based pharmacokinetic model for ACE inhibitors: ramipril and ramiprilat

The analysis of ramipril/ramiprilat concentration in human serum with liquid chromatography-tandem mass spectrometry – interpretation of high concentrations for the purposes of forensic toxicology

The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients

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