In vitro biotransformation of the analgesic agent, RWJ-51784, in rat, dog and human.
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.
Wu
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Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Spring House, PA 19477, USA.
McKown
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LA
Carson
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JR
D000700:Analgesics / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation / Q000502:physiology; D002227:Carbazoles / Q000737:chemistry / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism*; D051381:Rats
C482790:2-methyl-1,2,3,3a,4,5,6,10c-octahydropyrrolo(3,4-c)carbazole; D000700:Analgesics; D002227:Carbazoles; D011758:Pyrroles