TY - JOUR T1 - Role of Human UGT2B10 in <em>N</em>-Glucuronidation of Tricyclic Antidepressants, Amitriptyline, Imipramine, Clomipramine, and Trimipramine JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 863 LP - 870 DO - 10.1124/dmd.109.030981 VL - 38 IS - 5 AU - Diansong Zhou AU - Jian Guo AU - Alban J. Linnenbach AU - Catherine L. Booth-Genthe AU - Scott W. Grimm Y1 - 2010/05/01 UR - http://dmd.aspetjournals.org/content/38/5/863.abstract N2 - 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 Km (S50) values for the formation of quaternary N-glucuronides of amitriptyline, imipramine, clomipramine, and trimipramine were 2.60, 16.8, 14.4, and 11.2 μM in UGT2B10 and 448, 262, 112, and 258 μM 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 S50 values were similar to those found for expressed UGT1A4. The in vitro clearances (CLint or CLmax) were comparable between UGT2B10 and UGT1A4 for glucuronidation of imipramine, clomipramine, and trimipramine, whereas CLint of amitriptyline glucuronidation by UGT2B10 was more than 10-fold higher than that by UGT1A4. Nicotine was found to selectively inhibit UGT2B10 but not UGT1A4 activity. At a low tricyclic antidepressant concentration, nicotine inhibited their glucuronidation by 33 to 50% in human liver microsomes. Our results suggest that human UGT2B10 is a high-affinity enzyme for tricyclic antidepressant glucuronidation and is likely to be a major UGT isoform responsible for the glucuronidation of these drugs at therapeutic concentrations in vivo. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics ER -