Abstract

Growing evidence suggests that certain glucuronides function as potent inhibitors of cytochrome P450 (CYP) 2C8. 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-β-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-β-D-glucuronide formation in a candesartan concentration-dependent manner. Additionally, the uptake of candesartan N2-glucuronide and candesartan acyl-β-D-glucuronide by cells stably expressing OATPs is a saturable process with a K_m of 5.11 and 12.1 μM for OATP1B1 and 28.8 and 15.7 μM 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-β-D-glucuronide inhibit the CYP2C8-mediated metabolism of paclitaxel, with candesartan acyl-β-D-glucuronide exhibiting the strongest inhibition (the 50% inhibitory concentration (IC₅₀) is 18.9 µM for candesartan acyl-β-D-glucuronide, 150 µM for candesartan, and 166 µM for candesartan N2-glucuronide). However, time-dependent inhibition of CYP2C8 by candesartan acyl-β-D-glucuronide was not observed. Conversely, the IC₅₀ values of all the compounds are comparable for CYP3A4. Taken together, these data suggest that candesartan acyl-β-D-glucuronide is actively transported by OATPs into hepatocytes, and drug-drug interactions may occur with coadministration of candesartan and CYP2C8 substrates including paclitaxel as a result of the inhibition of CYP2C8 function.

Significance Statement This study demonstrates that the acyl glucuronidation of candesartan to form candesartan acyl-β-D-glucuronide enhances CYP2C8 inhibition while exerting minimal effects on CYP3A4, OATP1B1, and OATP1B3. Thus, candesartan acyl-β-D-glucuronide might represent a potential mediator of drug–drug interactions between candesartan and CYP2C8 substrates, such as paclitaxel, in clinical settings. This work adds to the growing knowledge regarding the inhibitory effects of glucuronides on CYP2C8.