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

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    Abstract

    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 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. © 2007 Springer Science+Business Media, LLC.
    Original languageEnglish
    Pages (from-to)1063-1074
    Number of pages11
    JournalPharmaceutical Research
    Volume25
    Issue number5
    DOIs
    Publication statusPublished - May 2008

    Keywords

    • CYP2C8
    • Drug-drug interactions
    • Enzyme inhibition
    • Gemfibrozil
    • OATP1B1

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