Wu Wu-Nan, McKown Linda A, Melton John L, Reitz Allen B
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Spring House, PA 19477, USA.
J Pharm Pharmacol. 2003 Aug;55(8):1099-105. doi: 10.1211/002235703322277122.
The in-vitro biotransformation of the anxiolytic agent, RWJ-50172 was studied after incubation with rat hepatic S9 fraction in the presence of an NADPH-generating system, and incubating with Cunninghamella echinulata in soy-bean medium. Unchanged RWJ-50172 (80% of the sample in rat; 86% in fungi) plus 6 metabolites (M1-M6) were profiled, quantified and tentatively identified on the basis of API-MS/MS data. The metabolic pathways for RWJ-50172 are proposed, and the four metabolic pathways are: pyrido-oxidation (pathway A), phenylhydroxylation (B), dehydration (C) and reduction (D). Pathway A formed hydroxy-pyrido-RWJ-50172 (M1, 10% of the sample in both rat and fungi) as the only major metabolite, which further dehydrated to form dehydro-RWJ-50172 in trace quantities in rat. Pathway B produced hydroxyphenyl-RWJ-50172 (M2) in small amounts (4%) in rat, and in conjunction with step A formed dihydroxy-RWJ-50172 as a trace metabolite in rat. Step D produced a minor benzimidazole-reduced metabolite in fungi. RWJ-50172 is substantially metabolized by this rat hepatic S9 fraction and fungi.
在存在NADPH生成系统的情况下，将抗焦虑药物RWJ - 50172与大鼠肝脏S9组分一起孵育，并在大豆培养基中与刺孢小克银汉霉一起孵育后，研究了其体外生物转化情况。根据API - MS/MS数据，对未变化的RWJ - 50172（大鼠样本中的80%；真菌中的86%）以及6种代谢产物（M1 - M6）进行了分析、定量和初步鉴定。提出了RWJ - 50172的代谢途径，这四种代谢途径为：吡啶氧化（途径A）、苯基羟基化（B）、脱水（C）和还原（D）。途径A形成羟基吡啶 - RWJ - 50172（M1，大鼠和真菌样本中的10%）作为唯一的主要代谢产物，其在大鼠中进一步脱水形成痕量的脱氢 - RWJ - 50172。途径B在大鼠中少量产生羟基苯基 - RWJ - 50172（M2）（4%），并与步骤A一起在大鼠中形成痕量代谢产物二羟基 - RWJ - 50172。步骤D在真菌中产生一种次要的苯并咪唑还原代谢产物。RWJ - 50172被这种大鼠肝脏S9组分和真菌大量代谢。
