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.

FIG. 1.

Mean (±SD) plasma concentration-time profiles of a single 600-mg oral dose of EFV (A and B) and 8-hydroxyefavirenz (8-hydroxyEFV) (C and D) in healthy volunteers (n = 10) treated with placebo pills (control; left panel) or rifampin (600 mg/day) (treated; right panel) for 10 days. Total represents conjugated plus unconjugated (β-glucuronidase treatment), and free represents unconjugated (no β-glucuronidase treatment).

FIG. 2.

Amounts of EFV and 8-hydroxyefavirenz (8-OHEFV) excreted over 12 h (Ae_0-12) after a single 600-mg oral dose of EFV in healthy volunteers (n = 10) treated with placebo pills (control) or rifampin (600 mg/day) for 10 days. Total and free represent conjugated plus unconjugated (β-glucuronidase [βG] treatment) and unconjugated (no β-glucuronidase treatment), respectively.