Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Antimicrob Agents Chemother. 2011 Apr;55(4):1504-9. doi: 10.1128/AAC.00883-10. Epub 2011 Jan 31.
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.
在这项研究中，评估了依非韦伦 N-葡萄糖醛酸化对依非韦伦体内消除的贡献。在一项两周期安慰剂对照交叉试验设计中，健康志愿者（n=10）预先服用安慰剂丸或每天 600mg 利福平口服 10 天，然后给予单剂量 600mg 口服依非韦伦。尿液和血浆中依非韦伦和 8-羟基依非韦伦的浓度通过液相色谱-串联质谱法测定，经过β-葡萄糖醛酸酶（共轭和非共轭）酶解和未经酶解（非共轭）。在安慰剂或利福平治疗组中，经酶解后获得的依非韦伦的药代动力学参数与未经酶解后获得的参数相比，没有任何统计学上的显著差异（P＞0.05；配对 t 检验，双侧）。在安慰剂和利福平治疗组中，12 小时内经酶解后排泄的依非韦伦量显著增加（P=0.007 和 P=0.0001），支持依非韦伦直接 N-葡萄糖醛酸化的发生，但由于尿中排泄的依非韦伦未改变或与共轭的量少于给予剂量的 1%，因此该发现的相关性有限。在安慰剂和利福平治疗组中，与未经酶解相比，8-羟基依非韦伦的血浆浓度和 12 小时内排泄量在经酶解后显著增加（P＜0.00001）。这些发现表明，尽管尿液数据支持依非韦伦直接发生 N-葡萄糖醛酸化，但依非韦伦 N-葡萄糖醛酸苷在血浆中的丰度可以忽略不计，并且 N-葡萄糖醛酸化途径对依非韦伦总体清除率的贡献似乎很小。
