In vitro evidence of potential interactions between CYP2C8 and candesartan acyl-β-d-glucuronide in the livers

Abstract

Growing evidence suggests that certain glucuronides function as potent inhibitors of CYP2C8. We previously reported the possibility of drug-drug interactions between candesartan cilexetil and paclitaxel. In this study, we evaluated the effects of candesartan N2-glucuronide and candesartan acyl-b-D-glucuronide on pathways associated with the elimination of paclitaxel, including those involving organic anion-transporting polypeptide (OATP) 1B1, OATP1B3, CYP2C8, and CYP3A4. UDP-glucuronosyltransferase (UGT) 1A10 and UGT2B7 were found to increase candesartan N2-glucuronide and candesartan acyl-b-D-glucuronide formation in a candesartan concentration-dependent manner. Additionally, the uptake of candesartan N2-glucuronide and candesartan acyl-b-Dglucuronide by cells stably expressing OATPs is a saturable process with Km of 5.11 and 12.1 mM for OATP1B1 and 28.8 and 15.7 mM for OATP1B3, respectively; both glucuronides exhibit moderate inhibition of OATP1B1/1B3. Moreover, the hydroxylation of paclitaxel was evaluated using recombinant CYP3A4 and CYP3A5. Results show that candesartan, candesartan N2-glucuronide, and candesartan acyl-b-D-glucuronide inhibit the CYP2C8-mediated metabolism of paclitaxel, with candesartan acyl-b-D-glucuronide exhibiting the strongest inhibition (IC50 is 18.9 mM for candesartan acyl-b-D-glucuronide, 150 mM for candesartan, and 166 mM for candesartan N2-glucuronide). However, time-dependent inhibition of CYP2C8 by candesartan acyl-b-D-glucuronide was not observed. Conversely, the IC50 values of all the compounds are comparable for CYP3A4. Taken together, these data suggest that candesartan acylb- D-glucuronide is actively transported by OATPs into hepatocytes, and drug-drug interactions may occur with coadministration of candesartan andCYP2C8 substrates, including paclitaxel, as a result of the inhibition of CYP2C8 function.