title: Contribution of N-glucuronidation to efavirenz elimination in vivo in the basal and rifampin-induced metabolism of efavirenz.
abstract: In this study, the contribution of efavirenz N-glucuronidation to efavirenz elimination in vivo was assessed. In a two-period placebo-controlled crossover trial design, a single 600-mg oral dose of efavirenz was administered to healthy volunteers (n = 10) pretreated with placebo pills or 600 mg/day rifampin orally for 10 days. Urine and plasma concentrations of efavirenz and 8-hydroxyefavirenz were measured by the liquid chromatography-tandem mass spectrometry method after enzymatic hydrolysis with β-glucuronidase (conjugated and unconjugated) and without enzymatic hydrolysis (unconjugated). Pharmacokinetic parameters of efavirenz within the placebo- or rifampin-treated group obtained after enzymatic hydrolysis did not show any statistically significant difference compared with those obtained without enzymatic hydrolysis (P > 0.05; paired t test, two-tailed). The amount of efavirenz excreted over 12 h was significantly larger after enzymatic hydrolysis in both the placebo (P = 0.007) and rifampin (P = 0.0001) treatment groups, supporting the occurrence of direct N-glucuronidation of efavirenz, but the relevance of this finding is limited because the amount of efavirenz excreted as unchanged or conjugated in urine is less than 1% of the dose administered. In both the placebo- and rifampin-treated groups, plasma concentrations of 8-hydroxyefavirenz and the amount excreted over 12 h were significantly larger (P < 0.00001) after enzymatic hydrolysis than without enzymatic hydrolysis. These findings suggest that although the occurrence of direct efavirenz N-glucuronidation is supported by the urine data, the abundance of efavirenz N-glucuronide in plasma is negligible and that the contribution of the N-glucuronidation pathway to the overall clearance of efavirenz seems minimal.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Doo-Yeoun
authors.initials: DY
authors.lastname: Cho
authors.forename: Evan T
authors.initials: ET
authors.lastname: Ogburn
authors.forename: David
authors.initials: D
authors.lastname: Jones
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
mesh_terms: D000328:Adult; D000480:Alkynes; D048588:Benzoxazines / Q000378:metabolism / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D003521:Cyclopropanes; D004311:Double-Blind Method; D005260:Female; D005966:Glucuronidase / Q000378:metabolism; D020719:Glucuronides / Q000378:metabolism*; D006801:Humans; D008297:Male; D012293:Rifampin / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D020719:Glucuronides; D005966:Glucuronidase; C098320:efavirenz; D012293:Rifampin