title: Effect of efavirenz on UDP-glucuronosyltransferase 1A1, 1A4, 1A6, and 1A9 activities in human liver microsomes.
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 K(i) values of 2.0 and 9.4 μM, respectively. [I]/K(i) 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 K(i) 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.
authors.affiliation: National Research Laboratory of Drug Metabolism & Bioanalysis, College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Korea.
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Ji
authors.forename: Hyeri
authors.initials: H
authors.lastname: Lee
authors.forename: Sae Rom
authors.initials: SR
authors.lastname: Lim
authors.forename: Jeong Han
authors.initials: JH
authors.lastname: Kim
authors.forename: Hye Suk
authors.initials: HS
authors.lastname: Lee
mesh_terms: D000480:Alkynes; D048588:Benzoxazines / Q000494:pharmacology*; D003521:Cyclopropanes; D057075:Enzyme Assays; D004958:Estradiol / Q000737:chemistry; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D015742:Propofol / Q000737:chemistry; D014268:Trifluoperazine / Q000737:chemistry; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D004958:Estradiol; D014453:Glucuronosyltransferase; D015742:Propofol; D014268:Trifluoperazine; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme; C000715591:UGT1A9 protein, human; C019787:bilirubin glucuronoside glucuronosyltransferase; C110655:UDP-glucuronosyltransferase, UGT1A6; C098320:efavirenz