Maximal inhibition of intestinal first-pass metabolism as a pragmatic indicator of intestinal contribution to the drug-drug interactions for CYP3A4 cleared drugs.

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 (F(G)(') and F(G), 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.

Multiple inhibition mechanisms and prediction of drug-drug interactions: status of metabolism and transporter models as exemplified by gemfibrozil-drug interactions.

Purpose: To assess the consequences of multiple inhibitors and differential inhibition mechanisms on the prediction of 12 gemfibrozil drug-drug interactions (DDIs). In addition, qualitative zoning of transporter-related gemfibrozil and cyclosporine DDIs was investigated.

Methods: The effect of gemfibrozil and its acyl-glucuronide on different enzymes was incorporated into a metabolic prediction model.