Gemfibrozil Glucuronidation in Human Liver Microsomes is Catalyzed by UDP-Glucuronosyltransferase 2B7V. Uchaipichat,* P.I. Mackenzie and J.O. Miners
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This study aimed to characterize the glucuronidation kinetics of gemfibrozil (GBZ) by human liver microsomes (HLMs) and to identify the human UDP-glucuronosyltransferase (UGT) enzymes responsible for these reactions. Using HLMs, the 2-Michaelis Menten kinetics were observed for GBZ glucuronidation with the mean high- and low-affinity apparent Km values of 5.6 ? 2.1 ?M (Vmax 444 ? 176 pmol/min.mg) and 316 ? 113 ?M (Vmax 1909 ? 838 pmol/min.mg), respectively. In addition, GBZ glucuronidation by HLMs was well described by a two-site model with mean derived binding affinity (Ks) and Vmax were 9.2 ? 3.2 ?M and 889 ? 437 pmol/min.mg, respectively. GBZ glucuronidation by UGT 1A3 (Km 386 ? 2 ?M) and 1A9 (Km 47 ? 0.3 ?M) exhibited Michaelis-Menten kinetics, whereas substrate inhibition (Km 378 ? 25 ?M and Ksi 2891 ? 319 ?M) was observed with UGT1A6. Similar to HLMs, GBZ glucuronidation by UGT2B7 was well described by the two-site kinetic model which provided a Ks value of 7.0 ? 0.9 ?M. Comparison of kinetic data suggests that UGT2B7 appears to be the enzyme responsible for the high-affinity component of human liver microsomal GBZ glucuronidation. These conclusions were confirmed using UGT2B7 (fluconazole) selective inhibitors.
Keyword:
COPD, drug counseling, pharmacy, Gemfibrozil, UDP-Glucuronosyltransferase, GBZ, human liver microsomes
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