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Human physiologically based pharmacokinetic model for ACE inhibitors: ramipril and ramiprilat by David G Levitt; Rik C Schoemaker is a Medicine article available to read on EtoBox.

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## Background The 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. ## Methods The 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. ## Results The PBP

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Author

David G Levitt; Rik C Schoemaker

Publisher

BioMed Central; Springer (Biomed Central Ltd.); London: BioMed Central, 2001-2012.; Springer Science and Business Media LLC (ISSN 1472-6904)

Published

2006

Language

EN

Field

Medicine (Health Sciences)