Chang M, Sood V K, Wilson G J, Kloosterman D A, Sanders P E, Schuette M R, Judy R W, Voorman R L, Maio S M, Slatter J G
Drug Metabolism and Disposition Research, Analytical and Medicinal Chemistry, Pharmacia & Upjohn, Inc., Kalamazoo, MI 49007, USA.
Drug Metab Dispos. 1998 Oct;26(10):1008-18.
Atevirdine mesylate (U-87201E) is a highly specific nonnucleoside inhibitor of human immunodeficiency virus type 1 reverse transcriptase. The absorption, metabolism, and excretion of atevirdine were investigated in male and female Sprague-Dawley rats after oral administration of nonradiolabeled atevirdine mesylate at doses of 20 mg/kg/day or 200 mg/kg/day for 8 days, with [14C]atevirdine mesylate single doses of 10 mg/kg or 100 mg/kg on study days 1 and 10. The distribution of [14C]atevirdine mesylate was also evaluated by whole-body autoradiography in male and female Sprague-Dawley, pregnant Sprague-Dawley, and male Long-Evans rats after a single 10 mg/kg oral dose. Plasma levels of atevirdine and its N-desethyl and O-desmethyl metabolites were determined by high-performance liquid chromatography (HPLC) with ultraviolet detection, urine and feces were profiled for atevirdine and metabolites by HPLC with radiochemical detection, major metabolites in urine were isolated and identified by nuclear magnetic resonance and mass spectrometry, and minor urinary metabolites were identified by liquid chromatography/mass spectrometry. Atevirdine was rapidly absorbed. The pharmacokinetics of atevirdine were nonlinear. Gender differences in the pharmacokinetics and metabolism of atevirdine were observed, consistent with the involvement of cytochrome P450 3A. Atevirdine effectively crossed the blood-brain barrier and had a high rate of maternal-fetal transfer. At the low doses, <2% of the dose was excreted as unchanged parent drug, while atevirdine constituted 9%-25% of the dose at the high doses. The metabolism of atevirdine was extensive in the rat and involved N-deethylation, O-demethylation, hydroxylation at the C-6 position of the indole ring, and hydroxylation of the pyridine ring.
甲磺酸阿替维啶（U-87201E）是一种高度特异性的1型人类免疫缺陷病毒逆转录酶非核苷抑制剂。在雄性和雌性斯普拉格-道利大鼠中，以20 mg/kg/天或200 mg/kg/天的剂量口服非放射性标记的甲磺酸阿替维啶8天，并在研究的第1天和第10天分别给予单剂量10 mg/kg或100 mg/kg的[14C]甲磺酸阿替维啶，研究了阿替维啶的吸收、代谢和排泄情况。还通过全身放射自显影技术，在雄性和雌性斯普拉格-道利大鼠、怀孕的斯普拉格-道利大鼠以及雄性朗-埃文斯大鼠口服单剂量10 mg/kg后，评估了[14C]甲磺酸阿替维啶的分布。通过高效液相色谱（HPLC）结合紫外检测法测定血浆中阿替维啶及其N-去乙基和O-去甲基代谢物的水平，通过HPLC结合放射化学检测法分析尿液和粪便中的阿替维啶及其代谢物，通过核磁共振和质谱法分离并鉴定尿液中的主要代谢物，通过液相色谱/质谱法鉴定尿液中的次要代谢物。阿替维啶吸收迅速。阿替维啶的药代动力学呈非线性。观察到阿替维啶在药代动力学和代谢方面存在性别差异，这与细胞色素P450 3A的参与一致。阿替维啶能有效穿过血脑屏障，且母婴转运率高。在低剂量时，<2%的剂量以未改变的母体药物形式排泄，而在高剂量时，阿替维啶占剂量的9%-25%。阿替维啶在大鼠体内的代谢广泛，涉及N-去乙基化、O-去甲基化、吲哚环C-6位的羟基化以及吡啶环的羟基化。
