RT Journal Article
SR Electronic
T1 In Vitro Evidence of Potential Interactions between CYP2C8 and Candesartan Acyl-<em>β</em>-D-glucuronide in the Liver
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 289
OP 297
DO 10.1124/dmd.120.000126
VO 49
IS 4
A1 Katsube, Yurie
A1 Tsujimoto, Masayuki
A1 Koide, Hiroyoshi
A1 Hira, Daiki
A1 Ikeda, Yoshito
A1 Minegaki, Tetsuya
A1 Morita, Shin-ya
A1 Terada, Tomohiro
A1 Nishiguchi, Kohshi
YR 2021
UL http://dmd.aspetjournals.org/content/49/4/289.abstract
AB 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-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 Km 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 (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, organic anion–transporting polypeptide (OATP) 1B1, 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.