Summary
The in vitro and in vivo metabolism of RWJ-53050, an anxiolytic agent, was investigated after incubation with rat and human hepatic S9 fractions, and human microsomes and 7 microsomes containing individual human CYP isoforms, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 in the presence of NADPH-generating system, and a single oral dose administration to dogs (30 mg/kg). Unchanged RWJ-53050 (≥74% of the sample in vitro; ⪯13% in vivo) plus 16 metabolites were profiled, quantified and tentatively identified based on the API-MS and MS/MS data. The formation of RWJ-53050 metabolites are via the 5 pathways: 1.N/O-demethylation, 2. phenylhydroxylation, 3. pyrido-oxidation, 4. dehydration, and 5. conjugation. Pathway 1 formedO-desmethyl-phenyl-RWJ-53050 (M1, <1–12% in vitro & in vivo), O-desmethyl-benzimidazole-RWJ-53050 (M2), and N-desmethyl-RWJ-53050 (M3) (M2 & M3, ⪯3% in vitro & in vivo). Pathway 2 generated hydroxy-benzimidazole-RWJ-53050 (M4), hydroxy-phenyl-RWJ-53050 (M5), and hydroxy-phenyl-M4 (M9) (⪯3% in vitro & in vivo). Pathway 3 formed 2 trace oxidized metabolites, hydroxy-pyrido-RWJ-53050 (M6, ⪯1% in vitro) and oxo-pyrido-RWJ-53050 (M8, <1% in vitro) and in conjunction with pathway 1 produced 2 trace dioxidized metabolites, OH-benzimidazole-M6 (M10) and OH-benzimidazole-M8 (M11) (in vitro). Pathway 4 formed a minor dehydrated metabolite of M6 (M7, 3%, in vitro). Pathway 5 produced 3 in vivo conjugates, Ml-glucuronide (M14,17%), M5-glucuronide (M15,50%), and M5-sulfate (M16,10%). RWJ-53050 is substantially metabolized in vitro in the rat and human, and extensively metabolized in vivo in the dog. formation of oxidized metabolites, Ml, M2, M4, M5 and M9.
Similar content being viewed by others
References
Maryanoff, B.E., McComsey, D.F., and Ho, W. ( 1993): 3-Oxopyrido[ 1,2- A]benzimidazole-4-carboxyl and4-oxoazepine [l,2-A]benzimidazole-5-carboxyl derivatives useful for treating central system disorders, US Patent 5,639,760
Maryanoff, B.E., Ho, W., McComsey, D.F., Reitz, A.B.. Grous, P.P., Nortey, S.O., Shank, R.P., Dubinsky, B., Taylor, Jr., R.J., and Gardocki, J.F. (1995): Potential anxiolytic agents, pyrido[l,2-o]benzimidazole: a new structural class of ligands for the benzodiazepine binding site on GABA-A receptors, J. Med. Chem., 38, 16–20.
Maryanoff, B.E., McComsey, D.F., Ho, W., Shank, R.P., and Dubinsky, B. (1996): Potential anxiolytic agents — II. Improvement of oral efficacy for the pyrido[ 1,2-α]benzimidazole (PBI) class of GABA-A receptor moderators, Bioorg. Med. Chem Lett., 6, 333–338.
Maryanoff, B.E., Nortey, S.O., McNally, J.J., Sanfilippo, P.J., McComsey, D.F., Dubinsky, B., Shank, R.P., and Reitz, A.B. (1999): Potential anxiolytic agents: 3. novel A-ring modified pyrido[1,2-α]benzimidazole, Bioorg. Med. Chem. Lett., 9, 1547–1552.
Reitz, A.B., Jordan, A.D., Sanfilippo, P.J., and Vaouyios-Smith, A. (1998): US Patent, 5,817,668,6.
Scott, M.K., Demeter, D.A., Nortey, S.O., Dubinsky. B., Shank, R.P., and Reitz, A.B. (1999): 4 New directions in anxiolytic drug research, Prog. Med. Chem., 36, 169–200.
Jordan, A.D., Vaidya, A.H., Rosenthal, D.I., Dubinsky, B., Kordik, C.P., Sanfilippo, P.J., Wu, W. N., and Reitz, A.B. (2002): Potential anxiolytic agents, part 4: novel orally-active N5-substituted pyrido[l,2-α]benzimidazoles with high GABA-A receptor affinity, Bioorg. Med. Chem. Lett., 12, 2381–2386.
Dubinsky, B., Vaidya, A.H., Rosenthal, D.I., Hochman, C, Crooke, J.J., Deluca, S., Devine, A., Cheo-Isaacs, CT., Carter, A.R., Jordan, A.D., Reitz, A.B., and Shank, R.P. (2002): 5-Ethoxymethyl-7-fluoro-3-oxo-1,2,3,5-tetrahy droben zo[4,5]imidazo[1,2α]-pyridine-4-N-(2-fluorophenyl)carboxamide (RWJ-51204), anew nonbenzodiazepine anxiolytic, J. Pharmacol. Exp. Ther, 303, 777–790.
Wu, W.N., McKown, L.A., and Takacs, A.R. (1998): In vitro metabolism of the anxiolytic agent, RWJ-53050, in rat and human hepatic S9 fractions, The 12th Inter. Sympos. on Microsom. and Drug Oxidat., Abstract No. 108.
Wu, W.N., McKown, L.A., Streeter, A.J., Takacs, A.R., and Reitz, A.B. (1998): Identifcation of metabolites and the cytochrome P450isoforms responsible for the metabolism of an anxiolytic agent, RWJ-53050, in human microsomes, The 12th Inter. Sympos. on Microsom. and Drug Oxidat., Abstract No. 107.
Wu, W.N., McKown, L.A., and Reitz, A.B. (2001): In vivo metabolism of the anxiolytic agent, RWJ-53050, in the dog, The 6th Internat.ISSX Meeting, Abstract No. 242, Drug Metab. Rev, 33, 123.
Wu, W.N., McKown, L.A., Melton, J.L., and Reitz, A.B. (2003): In vitro metabolism of the new anxiolytic agent, RWJ-50172, in rat hepatic S9 fraction and microbial transformation in fungi, Cunninghamella sp., J. Pharm, and Pharmacol., 55, 1099–1105.
Wu, W.N., McKown, L.A., and Reitz, A.B. (2003): in vitro metabolism of the new anxiolytic agent. RWJ-52763, in human hepatic s9 fraction — api-ms/ms identification of metabolites, J. Pharm, and Biomed. Analy., 31, 95–102.
Wu, W.N., McKown, L.A., and Reitz, A.B., (2004): Human hepatic metabolism of the anxiolytic agent, RWJ-51521 —api-ms/ms identification of metabolites, Europ. J. Drug Metab. and Pharmacok., 29, 257–262.
Wu, W.N., McKown, L.A., and Reitz, A.B. (2004):: Metabolism of the new nonbenzodiazepine anxiolytic agent, RWJ-51204, in mouse, rat, dog, monkey and human hepatic s9 fractions, and in rats, dogs and humans, Europ. J. Drug Metab. and Pharmacok., 29, 263–268.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Wu, WN., Mckown, L.A. & Reitz, A.B. Metabolism of the new anxiolytic agent, a pyrido[1,2-]benzimidazole (PBI) analog (RWJ-53050), in rat and human hepatic S9 fractions, and in dog; identification of cytochrome p450 isoforms mediated in the human microsomal metabolism. European Journal of Drug Metabolism and Pharmacokinetics 31, 277–283 (2006). https://doi.org/10.1007/BF03190468
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF03190468