| 20133892 |
Zhou D, Guo J, Linnenbach AJ, Booth-Genthe CL, Grimm SW: Role of Human UGT2B10 in N-Glucuronidation of Tricyclic Antidepressants, Amitriptyline, Imipramine, Clomipramine and Trimipramine. Drug Metab Dispos. 2010 Feb 4.
The role of human UGT2B10 in the N-glucuronidation of a number of tricyclic antidepressants was investigated and compared to that of UGT1A4 in both 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 muM in UGT2B10 and 448, 262, 112, and 258 muM in UGT1A4, respectively. The kinetics of amitriptyline and imipramine glucuronidation in human liver microsomes exhibited 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 UGT1A4. Nicotine was found to selectively inhibit UGT2B10 but not UGT1A4 activity. At low tricyclic antidepressants concentration, nicotine inhibited their glucuronidations by 33~50% in human liver microsomes. Our results suggest that human UGT2B10 is a high affinity enzyme for tricyclic antidepressants glucuronidation and is likely to be a major UGT isoform responsible for the glucuronidation of these drugs at therapeutic concentrations in vivo. |
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