Comparative analysis of CYP2C8-medidated drug-drug interactions produced by CYP2C8 inhibitors, gemfibrozil versus clopidogrel, focusing on the inhibition of drug distribution in UDP-glucuronosyltransferase prior to oxidation

Abstract

Purpose It is challenging to predict CYP2C8-mediated drug-drug interactions (DDIs) produced by clopidogrel (Clop) and gemfibrozil (Gem) by maintaining the victim’s fractional CYP2C8-mediated clearance (fm,CYP2C8) constant. The goal is to develop a comprehensive methodology for this. Method A model where UDP glucuronosyl transferase (UGT) and CYP work in pairs was devised, under the assumption that CYP2C8 substrates bind UGT before oxidation, and that Gem inhibits UGT and CYP2C8 while Clop inhibits CYP2C8 alone. Overall enzymatic inhibitory activity resulting from DDI was expressed as a function of fm,CYP2C8, fm,UGT (fractional UGT-mediated clearance), and perpetrator specific inhibitory activities against CYP2C8 and UGT (pAi,CYP2C8 and pAi,UGT(d)). Reported DDIs where Clop, Gem, or Gem + itraconazole have victimized montelukast, desloratadine, pioglitazone, repaglinide (OATP1B1 substrate) or cerivastatin (OATP1B1 substrate) were chosen for the analysis. Additionally, a method to simulate the victim’s plasma metabolite levels in response to the changes in the plasma unchanged drug levels was devised based on the previous method. Results The changes in the plasma levels of unchanged drug and metabolite produced by the DDIs were simulated successfully. The results confirmed the DDIs were not affected by the hepatic uptake transporter (OATP1B1). The pAi,CYP2C8 values for Clop and Gem were estimated to be 7 (85% inhibition) and 15 (93% inhibition). The pAi,UGT(d) values for Clop and Gem were estimated to be 1 (non-inhibition) and 2 (50% inhibition). Conclusions To predict CYP2C8 mediated DDIs, information on the victim’s fm,CYP2C8 and fm,UGT as well as the perpetrator’s pAi,CYP2C8 and pAi,UGT(d) are the most important.