Authors: Galetin, Aleksandra; Hinton, Laura K.; Burt, Howard; Obach, R. S.; Houston, J. B.r.i.a.n.

Source: Current Drug Metabolism, Volume 8, Number 7, October 2007 , pp. 685-693(9)

Publisher: Bentham Science Publishers

Abstract:

For certain CYP3A4 substrates intestinal first-pass metabolism makes a substantial contribution to low oral bioavailability and extent of drug-drug interactions (DDI). In order to include the contribution of enzyme inhibition in the gut wall in the assessment of DDI potential, the ratio of the intestinal wall availability in the presence and absence of an inhibitor (FG' and FG, respectively) has been incorporated into a prediction equation based on hepatic enzyme interactions. This approach has been applied for both reversible and irreversible DDIs, involving 36 different inhibitors and 11 CYP3A4 substrates. The aim was to investigate the use of maximal (complete) inhibition of intestinal CYP3A4 (FG'=1) as a pragmatic measure of the intestinal enzyme interaction and to compare this approach with observed in vivo values (where available) and predicted FG ratios from an intestinal model. The latter was obtained from the decrease in the intestinal intrinsic clearance in the presence of an inhibitor, using an estimated inhibitor concentration in the intestinal wall during absorption phase (IG) and an in vitro obtained Ki. In addition, the impact of variability in the enterocytic blood flow on the estimated IG and subsequently the model predicted FG ratio was investigated. The maximal FG ratios for the 11 CYP3A4 substrates investigated ranged from 1.06-7.14 for alprazolam and tacrolimus, respectively. In 91% of the studies investigated the model predicted FG ratio was within 40% of the maximal value. Maximal FG ratio is proposed as an initial indicator of the magnitude of intestinal enzyme interaction; the implications for drug elimination involving substrates cleared either by metabolism or by a combination of metabolism and efflux transporters are discussed.

Keywords: Intestinal first-pass; drug-drug interactions; CYP3A4; enzyme inhibition

Document Type: Research article

Publication date: 2007-10-01

More about this publication?

• Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:
  
  In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.

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