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

Yurie Katsube, Masayuki Tsujimoto, Hiroyoshi Koide, Daiki Hira, Yoshito Ikeda, Tetsuya Minegaki, Shin-ya Morita, Tomohiro Terada and Kohshi Nishiguchi
Drug Metabolism and Disposition January 14, 2021, DMD-AR-2020-000126; DOI: https://doi.org/10.1124/dmd.120.000126
Yurie Katsube
1pharmacy, Kyushu university hospital, Japan
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Masayuki Tsujimoto
2Department of Clinical Pharmacy, Kyoto Pharmaceutical University, Japan
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  • For correspondence: tsujimt@mb.kyoto-phu.ac.jp
Hiroyoshi Koide
3Pharmacy, Shiga University of Medical Science Hospital, Japan
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Daiki Hira
4Pharmaceutical Sciences, Ritsumeikan University, Japan
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Yoshito Ikeda
5Medicinal Cell Biology, Kobe Pharmaceutical University, Japan
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Tetsuya Minegaki
2Department of Clinical Pharmacy, Kyoto Pharmaceutical University, Japan
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Shin-ya Morita
3Pharmacy, Shiga University of Medical Science Hospital, Japan
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  • ORCID record for Shin-ya Morita
Tomohiro Terada
3Pharmacy, Shiga University of Medical Science Hospital, Japan
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Kohshi Nishiguchi
2Department of Clinical Pharmacy, Kyoto Pharmaceutical University, Japan
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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 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 (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.

  • CYP2C
  • CYP3A4
  • drug-drug interactions
  • Organic anion uptake / efflux (OATs, OATPs)
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (1)
Drug Metabolism and Disposition
Vol. 49, Issue 1
1 Jan 2021
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Candesartan glucuronide serves as a CYP2C8 inhibitor

Yurie Katsube, Masayuki Tsujimoto, Hiroyoshi Koide, Daiki Hira, Yoshito Ikeda, Tetsuya Minegaki, Shin-ya Morita, Tomohiro Terada and Kohshi Nishiguchi
Drug Metabolism and Disposition January 14, 2021, DMD-AR-2020-000126; DOI: https://doi.org/10.1124/dmd.120.000126

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Candesartan glucuronide serves as a CYP2C8 inhibitor

Yurie Katsube, Masayuki Tsujimoto, Hiroyoshi Koide, Daiki Hira, Yoshito Ikeda, Tetsuya Minegaki, Shin-ya Morita, Tomohiro Terada and Kohshi Nishiguchi
Drug Metabolism and Disposition January 14, 2021, DMD-AR-2020-000126; DOI: https://doi.org/10.1124/dmd.120.000126
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