Wu W N, McKown L A, Carson J R
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Spring House, PA 19477, USA.
Eur J Drug Metab Pharmacokinet. 2003 Apr-Jun;28(2):107-11. doi: 10.1007/BF03190497.
RWJ-51784, an analogue of phenyl isoindoles, is a new analgesic agent. The in vitro metabolism of RWJ-51784 was conducted using rat, dog and human hepatic S9 in the presence of an NADPH generating system, and API-ionspray-MS and MS/MS techniques for the metabolite profiling and identification. Unchanged RWJ-51784 (82, 80 & 86% of the sample in rat, dog & human, respectively) plus 6 metabolites were profiled and tentatively identified on the basis of MS data. RWJ-51784 metabolites were formed via the following 3 metabolic pathways: 1. N-demethylation, 2. phenylhydroxylation, and 3. isoindole-oxidation. Pathway 1 produced a moderate or minor metabolite, N-desmethyl-RWJ-51784 (M1; 6% in rat; 5% in dog, 2% in human). Pathway 2 formed 4-hydroxyphenyl-RWJ-51784 (M2; 3-6% in all species). Step 3 formed 2 isoindole-oxidized metaboliotes, OH-indole (M3; 7-8% in all species) and oxo-indole (M4; <1% in all species)-RWJ-51784, and in conjunction with pathway 2 produced 2 trace metabolites, OH-phenyl-OH-isoindole (M5) and OH-phenyl-oxo-isoindole (M6) metabolites. RWJ-51784 is not extensively metabolized in rat, dog and human hepatic S9 fractions.
RWJ - 51784是一种苯基异吲哚类似物，是一种新型镇痛药。在存在NADPH生成系统的情况下，使用大鼠、犬和人肝脏S9进行RWJ - 51784的体外代谢研究，并采用API - 离子喷雾质谱和串联质谱技术进行代谢产物的谱图分析和鉴定。根据质谱数据，对未变化的RWJ - 51784（分别占大鼠、犬和人样品的82%、80%和86%）以及6种代谢产物进行了谱图分析并初步鉴定。RWJ - 51784的代谢产物通过以下3条代谢途径形成：1. N - 去甲基化；2. 苯基羟基化；3. 异吲哚氧化。途径1产生一种中度或少量的代谢产物N - 去甲基 - RWJ - 51784（M1；大鼠中占6%；犬中占5%，人中占2%）。途径2形成4 - 羟基苯基 - RWJ - 51784（M2；在所有物种中占3 - 6%）。步骤3形成2种异吲哚氧化代谢产物，OH - 吲哚（M3；在所有物种中占7 - 8%）和氧代 - 吲哚（M4；在所有物种中均<1%） - RWJ - 51784，并且与途径2一起产生2种痕量代谢产物，OH - 苯基 - OH - 异吲哚（M5）和OH - 苯基 - 氧代 - 异吲哚（M6）代谢产物。RWJ - 51784在大鼠、犬和人肝脏S9组分中未发生广泛代谢。
