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Title of Journal: Pharm Res

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Abbravation: Pharmaceutical Research

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Springer US

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DOI

10.1002/chin.198946201

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1573-904X

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Multiple Inhibition Mechanisms and Prediction of D

Authors: Laura K Hinton Aleksandra Galetin J Brian Houston
Publish Date: 2007/09/27
Volume: 25, Issue: 5, Pages: 1063-1074
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Abstract

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 transporterrelated gemfibrozil and cyclosporine DDIs was investigatedThe effect of gemfibrozil and its acylglucuronide on different enzymes was incorporated into a metabolic prediction model The impact of CYP2C8 timedependent inhibition by gemfibrozil acylglucuronide 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 Iin were used for qualitative zoning of 14 transportermediated DDIsIncorporation of timedependent 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 overpredictedTimedependent inhibition by gemfibrozil glucuronide is only important for victim drugs eliminated predominantly 80 via CYP2C8 Qualitative zoning of OATP1B1 inhibitors based on Iin/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

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