Balani S K, Kauffman L R, Arison B H, Olah T V, Goldman M E, Varga S L, O'Brien J A, Ramjit H G, Rooney C S, Hoffman J M
Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486.
Drug Metab Dispos. 1994 Mar-Apr;22(2):200-5.
Healthy subjects were administered single oral doses of 800 mg or 400 mg 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-o ne (L-696,229), a nonnucleoside inhibitor of the human immunodeficiency virus-type 1 (HIV-1) reverse transcriptase (RT). Plasma or urine samples were collected over a period of 48 hr. Pooled plasma (0.5-6 hr) and urine (0-24 hr) samples were analyzed by HPLC-UV and HIV-1 RT inhibition assay using poly rC.dG as a template primer. The parent compound and several common metabolites were detected in both samples. The metabolic profiles were also similar to those obtained from a rat liver slice incubation with [3H]L-696,229. The in vitro metabolites were identified by NMR and MS as 5 alpha-hydroxyethyl- (major), 5,6-dihydrodiol-, 6'-hydroxy-, 6-hydroxymethyl-, and 5-vinyl analogs, and a benzoxazole ring hydrolysis product. Most of the significant metabolites in human plasma and urine were found to be identical to the in vitro metabolites, as established by HPLC-UV and MS. Hydrolysis of the plasma and urine with beta-glucuronidase/sulfatase indicated the presence of significant amounts of conjugates of the parent compound and 5 alpha-hydroxyethyl metabolite. Most of the other primary metabolites were also present in conjugated forms, albeit in small quantities. In addition, two secondary metabolites were isolated and identified from the hydrolyzed urine as 5-acetyl-6'-hydroxy- and 5 alpha-hydroxyethyl-6-hydroxymethyl- analogs.(ABSTRACT TRUNCATED AT 250 WORDS)
健康受试者口服单剂量800毫克或400毫克的3-[2-(苯并恶唑-2-基)乙基]-5-乙基-6-甲基吡啶-2(1H)-酮(L-696,229)，一种人类免疫缺陷病毒1型(HIV-1)逆转录酶(RT)的非核苷抑制剂。在48小时内收集血浆或尿液样本。合并的血浆(0.5 - 6小时)和尿液(0 - 24小时)样本通过HPLC-UV和使用聚rC.dG作为模板引物的HIV-1 RT抑制试验进行分析。在两个样本中均检测到母体化合物和几种常见代谢物。代谢谱也与用[3H]L-696,229进行大鼠肝切片孵育所获得的谱相似。通过NMR和MS将体外代谢物鉴定为5α-羟乙基-(主要)、5,6-二氢二醇-、6'-羟基-、6-羟甲基-和5-乙烯基类似物，以及一种苯并恶唑环水解产物。通过HPLC-UV和MS确定，人血浆和尿液中的大多数主要代谢物与体外代谢物相同。用β-葡萄糖醛酸酶/硫酸酯酶对血浆和尿液进行水解表明存在大量母体化合物和5α-羟乙基代谢物的共轭物。大多数其他主要代谢物也以共轭形式存在，尽管数量较少。此外，从水解尿液中分离并鉴定出两种次要代谢物为5-乙酰基-6'-羟基-和5α-羟乙基-6-羟甲基-类似物。(摘要截短于250字)
