title: Hepatic metabolism of two alpha-1A-adrenergic receptor antagonists, phthalimide-phenylpiperazine analogs (RWJ-69205 and RWJ-69471), in the rat, dog and human.
abstract: The In vitro metabolism of two alpha-1A-adrenergic antagonists, RWJ-69205 and RWJ-69471 (phthalimide-phenylpiperazine analogs), was assessed after 30 and 60 min incubations with rat, dog and human hepatic S9 fractions in the presence of an NADPH-generating system. Unchanged RWJ-69205 (> or = 72% of the sample in all species) plus 3 metabolites from the RWJ-69205 incubations, and unchanged RWJ-69471 (> or = 60% of the sample in all species) and 7 metabolites from the RWJ-69471 incubations, were profiled, quantified, and tentatively identified on the basis of API-MS and MS/MS data. The formation of RWJ-69205 and RWJ-69471 metabolites are via the following five metabolic pathways: 1. phenylhydroxylation, 2. O-dealkylation, 3. oxidative N-dealkylation, 4. N-dephenylation, and 5. dehydration. Pathway 1 formed 2 major/moderate hydroxy-phenyl metabolites of 2 analogs (4-17%) in all species, and pathway 2 produced 2 O-desisopropyl metabolites of 2 analogs in major/moderate (7-16%) in rat and human, and in trace (< 1%) in dog; in conjunction with pathway 1, yielded a minor diphenolic metabolite (< 1-2%) in RWJ-69471. Pathway 3 formed a minor N-dealkylated metabolite, isopropoxyphenyl piperazine (< 1-6%) in all species of 2 analogs. Pathways 4 and 5 produced 2 minor N-desphenyl metabolite and dehydrated metabolite, respectively, in rat and human S9 (< or = 1-2%) in RWJ-69471. Both RWJ-69205 and RWJ-69471 were less extensively metabolized in the dog. However, rat and human appeared to metabolize RWJ-69471 more extensively than RWJ-69205 in this hepatic system.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Spring House, PA 19477, USA.
authors.forename: W N
authors.initials: WN
authors.lastname: Wu
authors.forename: L A
authors.initials: LA
authors.lastname: McKown
authors.forename: G H
authors.initials: GH
authors.lastname: Kuo
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003640:Dealkylation; D004285:Dogs; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D054833:Isoindoles; D008099:Liver / Q000378:metabolism*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010797:Phthalimides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D053719:Tandem Mass Spectrometry / Q000379:methods; D013997:Time Factors
chemical_list: C518748:2-(3-fluorophenyl)-2,3-dihydro-N-(2-hydroxy-3-(4-(2-(1-methylethoxy)phenyl)-1-piperazinyl)propyl)-1,3-dioxo-1H-isoindole-5-carboxamide; C518749:2-(4-methylphenyll)-2,3-dihydro-N-(2-hydroxy-3-(4-(2-(1-methylethoxy)phenyl)-1-piperazinyl)propyl)-1,3-dioxo-1H-isoindole-5-carboxamide; C547713:ADRA1A protein, human; C547715:Adra1a protein, rat; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D054833:Isoindoles; D010797:Phthalimides; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; C037431:phthalimide; C031503:phenylpiperazine