Wu Wu-Nan, McKown Linda A, Reitz Allen B
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Welsh McKean Rds, PO Pox 776, Spring House, PA 19477, USA.
J Pharm Biomed Anal. 2003 Feb 5;31(1):95-102. doi: 10.1016/s0731-7085(02)00597-6.
The in vitro metabolism of the anxiolytic agent, RWJ-52763 was studied after incubation with human hepatic S9 fraction in the presence of an NADPH-generating system. Unchanged RWJ-52763 (64% of the sample) plus six metabolites (M1-M6) were profiled, quantified, and tentatively identified on the basis of API-MS/MS data. The metabolic pathways for RWJ-52763 are proposed, and the two metabolic pathways are: (1) N/O-dealkylation, and (2) phenylhydroxylation. Pathway 1 formed a major N-dealkylated metabolite, N-desethoxy-RWJ-52763 (M1, 22% of the sample) and 2 minor N/O-dealkylated metabolites, O-desmethyl-RWJ-52763 (M2; 2%) and N,N-didesethoxymethyl-RWJ-52763 (M3; 3%). Pathway 2 produced two hydroxyphenyl metabolites, hydroxydifluorophenyl-RWJ-52763 (M4; 4%) and hydroxyphenyl-pyrido-RWJ-52763 (M5; 3%) in small amounts, and in conjunction with step 1 formed a minor N-desethoxymethyl-M4 (M6; 1%). RWJ-52763 is substantially metabolized by this human hepatic S9.
在存在NADPH生成系统的情况下，将抗焦虑药RWJ-52763与人肝S9组分一起孵育后，对其体外代谢情况进行了研究。根据API-MS/MS数据，对未变化的RWJ-52763（占样品的64%）以及六种代谢产物（M1-M6）进行了分析、定量并初步鉴定。提出了RWJ-52763的代谢途径，这两条代谢途径为：（1）N/O-脱烷基化，以及（2）苯基羟基化。途径1形成了一种主要的N-脱烷基代谢产物，N-去乙氧基-RWJ-52763（M1，占样品的22%）和两种次要的N/O-脱烷基代谢产物，O-去甲基-RWJ-52763（M2；2%）和N,N-二去乙氧基甲基-RWJ-52763（M3；3%）。途径2产生了两种少量的羟基苯基代谢产物，羟基二氟苯基-RWJ-52763（M4；4%）和羟基苯基-吡啶-RWJ-52763（M5；3%），并且与步骤1一起形成了一种次要的N-去乙氧基甲基-M4（M6；1%）。RWJ-52763在这种人肝S9中被大量代谢。
