Potential role of intestinal first-pass metabolism in the prediction of drug–drug interactions
- 15 July 2008
- journal article
- review article
- Published by Taylor & Francis Ltd in Expert Opinion on Drug Metabolism & Toxicology
- Vol. 4 (7), 909-922
- https://doi.org/10.1517/17425255.4.7.909
Abstract
Background: The contribution of intestine to the magnitude of drug–drug interactions (DDI) may be significant, considering high levels of inhibitors in the gut lumen achieved during absorption and the abundance of metabolic enzymes in the mature enterocytes. Intestinal inhibition is incorporated in the DDI prediction models as the ratio of the intestinal wall availability in the presence and absence of the inhibitor (FG′ and FG, respectively). Objective: This review will focus on the ability of the current approaches to estimate the extent of intestinal DDI accurately, addressing predominantly the most abundant intestinal P450 enzyme, CYP3A4. Methods: Considering the sensitivity of the DDI prediction models to the accuracy of the FG estimates, the current study focuses on 3 different in vitro and in vivo approaches to assess this parameter. Results/conclusion: The advantages and limitations of each of FG methods are outlined. Accurate assessment of this parameter is essential for the prediction of human drug clearance and drug–drug interaction potential.Keywords
This publication has 116 references indexed in Scilit:
- Species Differences in In Vitro and In Vivo Small Intestinal Metabolism of CYP3A SubstratesJournal of Pharmaceutical Sciences, 2008
- Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjectsBritish Journal of Clinical Pharmacology, 2008
- Application of CYP3A4 in vitro data to predict clinical drug–drug interactions; predictions of compounds as objects of interactionBritish Journal of Clinical Pharmacology, 2008
- Interaction between midazolam and clarithromycin in the elderlyBritish Journal of Clinical Pharmacology, 2007
- Intestinal and Hepatic Metabolic Activity of Five Cytochrome P450 Enzymes: Impact on Prediction of First-Pass MetabolismThe Journal of pharmacology and experimental therapeutics, 2006
- THE HUMAN INTESTINAL CYTOCHROME P450 “PIE”Drug Metabolism and Disposition, 2006
- MODELING OF INTESTINAL DRUG ABSORPTION: ROLES OF TRANSPORTERS AND METABOLIC ENZYMES (FOR THE GILLETTE REVIEW SERIES)Drug Metabolism and Disposition, 2003
- Hepatic and intestinal cytochrome P450 3A activity in cirrhosis: Effects of transjugular intrahepatic portosystemic shuntsJournal of Hepatology, 2001
- Effect of Grapefruit Juice on the Pharmacokinetics of Microemulsion Cyclosporine and its Metabolite in Healthy Volunteers: Does the Formulation Difference Matter?The Journal of Clinical Pharmacology, 1998
- Clearance concepts in pharmacokineticsJournal of Pharmacokinetics and Biopharmaceutics, 1973