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.