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. The aim was to investigate the use of maximal (complete) inhibition of intestinal CYP3A4 (F(G)(')=1) as a pragmatic measure of the intestinal enzyme interaction and to compare this approach with observed in vivo values (where available) and predicted F(G) 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 (I(G)) and an in vitro obtained K(i). In addition, the impact of variability in the enterocytic blood flow on the estimated I(G) and subsequently the model predicted F(G) ratio was investigated. The maximal F(G) 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 F(G) ratio was within 40% of the maximal value. Maximal F(G) 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.

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. The impact of CYP2C8 time-dependent inhibition by gemfibrozil acyl-glucuronide was assessed using repaglinide, cerivastatin, loperamide, rosiglitazone and pioglitazone DDIs. Gemfibrozil and cyclosporine inhibition data obtained in human embryonic kidney cells expressing OATP1B1 and hepatic input concentration ([I]in) were used for qualitative zoning of 14 transporter-mediated DDIs. RESULTS: Incorporation of time-dependent inhibition by gemfibrozil glucuronide showed no significant improvement in the prediction, as CYP2C8 contributed <65% to the overall elimination of the victim drugs investigated. Qualitative zoning of OATP1B1 DDIs resulted in no false negative predictions; yet the magnitude of observed interactions was significantly over-predicted. CONCLUSIONS: Time-dependent inhibition by gemfibrozil glucuronide is only important for victim drugs eliminated predominantly (>80%) via CYP2C8. Qualitative zoning of OATP1B1 inhibitors based on [I]in/K (i) is valid in drug screening to avoid false negatives. Refinement of the transporter model by incorporating the fraction of drug transported by a particular transporter is recommended.