Role of human UGT2B10 in N-glucuronidation of tricyclic antidepressants, amitriptyline, imipramine, clomipramine, and trimipramine

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Diansong ZhouScott W Grimm

Abstract

The role of human UDP glucuronosyltransferase (UGT) 2B10 in the N-glucuronidation of a number of tricyclic antidepressants was investigated and compared with that of UGT1A4 in both the Sf9 expressed system and human liver microsomes. The apparent K(m) (S(50)) values for the formation of quaternary N-glucuronides of amitriptyline, imipramine, clomipramine, and trimipramine were 2.60, 16.8, 14.4, and 11.2 microM in UGT2B10 and 448, 262, 112, and 258 microM in UGT1A4, respectively. The kinetics of amitriptyline and imipramine glucuronidation in human liver microsomes exhibited a biphasic character, where the high- and low-affinity components were in good agreement with our results in expressed UGT2B10 and UGT1A4, respectively. The kinetics of clomipramine and trimipramine glucuronidation in human liver microsomes were sigmoidal in nature, and the S(50) values were similar to those found for expressed UGT1A4. The in vitro clearances (CL(int) or CL(max)) were comparable between UGT2B10 and UGT1A4 for glucuronidation of imipramine, clomipramine, and trimipramine, whereas CL(int) of amitriptyline glucuronidation by UGT2B10 was more than 10-fold higher than that by UGT1A4. Nicotine was found to selectively inhibit UGT2B10 but not UGT1A...Continue Reading

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Citations

Mar 24, 2015·Expert Opinion on Drug Metabolism & Toxicology·Zoe Riches, Abby C Collier
Oct 23, 2014·Drug Metabolism Reviews·Dong Gui HuPeter I Mackenzie
Mar 26, 2011·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Sanna KaivosaariMikko Koskinen
Apr 23, 2014·Biopharmaceutics & Drug Disposition·Eriko HigashiYohei Miyamoto
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Jul 27, 2015·Drug Metabolism and Pharmacokinetics·Masaya SakamotoRyoichi Fujiwara
Feb 17, 2015·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Julieta GradinaruSerge Rudaz
Mar 12, 2015·Drug Metabolism and Pharmacokinetics·Shingo OdaMiki Nakajima
Jun 17, 2016·Expert Opinion on Drug Metabolism & Toxicology·Chiara FabbriAlessandro Serretti
Feb 13, 2018·Clinical and Experimental Pharmacology & Physiology·Ji RuanChang Sun
Jul 28, 2018·Expert Opinion on Drug Metabolism & Toxicology·Danyi LuBaojian Wu
Feb 7, 2019·Physiological Reviews·Robyn MeechPeter I Mackenzie
Feb 14, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Adrien LabrietChantal Guillemette
Feb 25, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Shinsuke UchihashiToshiyuki Sakaki
Apr 25, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yukiko KatoMiki Nakajima
Dec 17, 2014·The Journal of Pharmacology and Experimental Therapeutics·Stephen FowlerVictor A Iglesias
Dec 17, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Nicolo MilaniStephen Fowler
Dec 24, 2019·Acta Pharmaceutica Sinica. B·Yuhua LiHuichang Bi

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