Stereoselective glucuronidation and hydroxylation of etodolac by UGT1A9 and CYP2C9 in man

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
K TougouA Nakamura

Abstract

1. In vitro metabolic studies with etodolac were performed. S- and R-etodolac were converted to the acylglucuronide and hydroxylated metabolites by UDP-glucuronosyltransferase (UGT) and cytochrome P450 in microsomes. However, the stereoselectivities of UGT and P450 for the isomers were opposite. S-etodolac was glucuronidated preferentially than R-etodolac by UGT. In contrast, R-etodolac was hydroxylated preferentially than S-etodolac by P450. 2. Of several human P450 enzymes, CYP2C9 had the greatest activity for hydroxylation of R-etodolac. Sulfaphenazole, an inhibitor of CYP2C9, and anti-CYP2C9 antibody inhibited the hydroxylation of R-etodolac in human liver microsomes. CYP2C9 therefore contributes to the stereoselective hydroxylation of R-etodolac. 3. Of several human UGT enzymes, UGT1A9 had the greatest activity for glucuronidation of S-etodolac. Propofol and thyroxine, inhibitors of UGT1A9, inhibited the glucuronidation of S-etodolac in human liver microsomes. Therefore, UGT1A9 is mainly responsible for the stereoselective glucuronidation of S-etodolac. 4. Because S-etodolac was metabolized more rapidly than R-etodolac in human cryopreserved hepatocytes, the stereoselectivities of UGT1A9 for etodolac substantially influenc...Continue Reading

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Citations

Aug 13, 2008·Analytical and Bioanalytical Chemistry·Ulrich M ZangerMatthias Schwab
Jan 25, 2007·European Journal of Clinical Pharmacology·Yuji ManoHidetaka Kamimura
Jun 5, 2010·Chemical & Pharmaceutical Bulletin·Shenggu Xie, Su Zeng
Mar 16, 2011·Drug Metabolism and Pharmacokinetics·Noriyuki Koyama, Yasushi Yamazoe
Sep 6, 2013·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hyeon-Uk JeongHye Suk Lee
Sep 4, 2015·Clinical Pharmacokinetics·Prajakta S BadriRajeev M Menon
Jan 2, 2016·Journal of Pharmaceutical and Biomedical Analysis·Carolina de Miranda SilvaVera Lucia Lanchote
Jan 2, 2016·Pharmacological Reviews·Janne T BackmanPertti J Neuvonen
Mar 10, 2018·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Ugo ZanelliCarl Petersson
Feb 27, 2018·Cancer Medicine·Xiangkun WangTao Peng
Jan 19, 2012·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hye Young JiHye Suk Lee
Sep 15, 2018·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·In-Hwan Baek
Apr 26, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yuki KutsunoRyoichi Fujiwara
Apr 21, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yuji ManoHidetaka Kamimura

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