Abstract: Efavirenz is a non-nucleoside reverse transcriptase inhibitor used for the treatment of human immunodeficiency virus type 1 infections. Drug interactions of efavirenz have been reported due to in vitro inhibition of CYP2C9, CYP2C19, CYP3A4, and UDP-glucuronosyltransferase 2B7 (UGT2B7) and in vivo CYP3A4 induction. The inhibitory potentials of efavirenz on the enzyme activities of four major UDP-glucuronosyltransferases (UGTs), 1A1, 1A4, 1A6, and 1A9, in human liver microsomes were investigated using liquid chromatography-tandem mass spectrometry. Efavirenz potently inhibited UGT1A4-mediated trifluoperazine N-glucuronidation and UGT1A9-mediated propofol glucuronidation, with Ki values of 2.0 and 9.4 μM, respectively. [I]/Ki ratios of efavirenz for trifluoperazine N-glucuronidation and propofol glucuronidation were 6.5 and 1.37, respectively. Efavirenz also moderately inhibited UGT1A1-mediated 17β-estradiol 3-glucuronidation, with a Ki value of 40.3 μM, but did not inhibit UGT1A6-mediated 1-naphthol glucuronidation. Those in vitro results suggest that efavirenz should be examined for potential pharmacokinetic drug interactions in vivo due to strong inhibition of UGT1A4 and UGT1A9.
Keywords: efavirenz; UDP-glucuronosyltransferase inhibition; human liver microsomes; drug-drug interaction
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Ji, H.Y.; Lee, H.; Lim, S.R.; Kim, J.H.; Lee, H.S. Effect of Efavirenz on UDP-Glucuronosyltransferase 1A1, 1A4, 1A6, and 1A9 Activities in Human Liver Microsomes. Molecules 2012, 17, 851-860.
Ji HY, Lee H, Lim SR, Kim JH, Lee HS. Effect of Efavirenz on UDP-Glucuronosyltransferase 1A1, 1A4, 1A6, and 1A9 Activities in Human Liver Microsomes. Molecules. 2012; 17(1):851-860.
Ji, Hye Young; Lee, Hyeri; Lim, Sae Rom; Kim, Jeong Han; Lee, Hye Suk. 2012. "Effect of Efavirenz on UDP-Glucuronosyltransferase 1A1, 1A4, 1A6, and 1A9 Activities in Human Liver Microsomes." Molecules 17, no. 1: 851-860.