In vitro glucuronidation of the primary metabolite of 10-chloromethyl-11-demethyl-12-oxo-calanolide A by human liver microsomes and its interactions with UDP-glucuronosyltransferase substrates

Drug Metabolism and Pharmacokinetics
Xin LiuYan Li

Abstract

F18 (10-chloromethyl-11-demethyl-12-oxo-calanolide), an analog of (+)-Calanolide A, is a novel small-molecule nonnucleoside reverse transcriptase inhibitor for the therapy of human immunodeficiency virus (HIV) infection. M3, the most abundant primary metabolite of F18 in human liver microsomes (HLMs) and rat liver microsomes (RLMs), is mainly excreted in bile as a glucuronide conjugate in rats after oral administration. The aim of this study was to identify the UDP glucuronosyltransferase (UGT) isoforms involved in the glucuronidation of M3 by HLMs and recombinant human UGTs and investigate the metabolic interactions of M3 with the substrates of UGTs in HLMs. As a result, UGT1A1 was the major isozyme responsible for the glucuronidation of M3, followed by UGT1A4, UGT1A9 and UGT2B7. M3 exhibited significant inhibition against UGT1A9 and UGT2B7 in both HLMs and recombinant human UGTs. In addition, M3 inhibited UGT1A9 catalyzed mycophenolic acid (MPA) glucuronidation with Ki of 0.39 μM, and M3 also inhibited the glucuronidation of 3'-azido-3'-deoxythymidine (AZT) by a "mixed-type" mechanism with Ki of 16.8 μM. The results suggest that UGT1A1 provides the major contribution to M3 glucuronidation in vitro and M3 has the potential to i...Continue Reading

References

Feb 1, 1990·British Journal of Clinical Pharmacology·O Z BarakaC J Roberts
Jul 1, 1998·Clinical Pharmacokinetics·R E BullinghamB R Kamm
Jul 8, 1998·Proceedings of the National Academy of Sciences of the United States of America·E BeutlerA Demina
Jun 3, 2000·Annual Review of Pharmacology and Toxicology·R H Tukey, C P Strassburg
Mar 29, 2001·Journal of Pharmaceutical and Biomedical Analysis·N HaniokaM Ando
Mar 19, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Anthony Y H LuJiunn H Lin
Jun 20, 2003·The Pharmacogenomics Journal·C Guillemette
Aug 12, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·J Andrew WilliamsSimon E Ball
Mar 23, 2005·Pharmacology & Therapeutics·Tony K L KiangThomas K H Chang
May 19, 2005·Toxicological Reviews·Rupika Delgoda, Andrew C G Westlake
Jul 27, 2005·Therapeutic Drug Monitoring·Richard BorrowsDavid Taube
Sep 6, 2005·Pharmacogenetics and Genomics·Peter I MackenzieDaniel W Nebert
Dec 25, 2007·Bioorganic & Medicinal Chemistry Letters·Tao MaGang Liu
Jun 25, 2008·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Hui-Xin LiuLing Yang
Jun 3, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Anne-Sophie BélangerChantal Guillemette
Oct 24, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yong LiuMark J Ratain
Aug 23, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Nenad ManevskiMoshe Finel
May 1, 2012·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yong-Sheng ZhangHai-Rong Li
Jun 6, 2012·Current Drug Safety·Paulino Antonio AlvarezGuillermo Alberto Keller
May 25, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hyo-Ji KimDong-Hyun Kim
Sep 7, 2013·Journal of the International AIDS Society·Iris UsachJosé-Esteban Peris
Mar 19, 2014·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Yu Fen ZhengSoo Kyung Bae

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