In vitro metabolism of the analgesic agent, RWJ-37874, in rat and human

RWJ-37874, an analogue of aroyl(aminoacyl)pyrrole, is a new analgesic agent. The in vitro metabolism of RWJ-37874 was conducted using rat and human hepatic S9 in the presence of an NADPH generating system, and API-ionspray-MS and MS/MS techniques for metabolite profiling and identification. Unchanged RWJ-37874 (66 & 86% of the sample in rat & human, respectively) plus four metabolites were profiled and tentatively identified on the basis of MS data. RWJ-37874 metabolites were formed via the following two metabolic pathways: 1. oxidative N-deethylation, and 2. pyrrole-oxidation. Pathway 1 produced a mayor and a minor metabolites, N-desethyl-RWJ-37874 (M1; 34% in rat; 13% in human) and N,N-didesethyl-RWJ-37874 (M3; <0.5% in both species), respectively. Pathway 2 formed hydroxypyrrole-RWJ-37874 (M2; <0.5% in all species), and in conjunction with step 1, formed hydroxy-M1 (M4; <0.5% in rat). RWJ-37874 is substantially metabolized in rat and human hepatic S9 fractions. However, rat appears to metabolize RWJ-37874 more extensively than human via N-dealkylation forming N-desethyl-RWJ-37874 as a major metabolite.