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

  • W. N. Wu
  • L. A. McKown
  • A. B. Reitz


The in vitro and in vivo metabolism of the nonbenzodiazepine anxiolytic agent, RWJ-51204 was investigated after incubation with mice, rat, dog, monkey, and human hepatic S9 fractions in the presence of NADPH-generating system, and a single oral dose administration to rats (100 mg/kg), dogs (5 mg/kg), and humans (2.5 mg/subject). Plasma and red blood cells (2 h, rat) and urine samples (0–24 h, rat, dog and human) were obtained postdose. Unchanged RWJ-51204 (39–93% of the sample in vitro; ≤5% of the sample in vivo) plus 14 metabolites were profiled, quantified and tentatively identified on the basis of API-MS and MS/MS data, and by comparison of synthetic samples.

The in vitro and in vivo metabolic pathways for RWJ-51204 are proposed, and the metabolite formations are via the following five pathways: 1. phenyl oxidation, 2. pyrido-oxidation, 3. N-deethoxymethylation, 4. dehydration, and 5. glucuronidation. Pathway 1 formed 4-hydroxy-2-fluoro-phenyl-RWJ-51204 (Ml, 7–24% in vitro; 5–60% in vivo) in major amounts, OH-benzimidazole-RWJ-51204 (M2, 5–8% in vitro and in vivo) and diOH-phenyl-RWJ-51204 (≤5–16% in vitro and in vivo); in conjunction with pathway 5 produced Ml glucuronide (60% in rat & dog; 17% in human), M2 glucuronide (16% in human). Pathways 2–4 formed minor/trace oxidized, and dehydrated metabolites. RWJ-51204 is extensively metabolized in vitro (except dog) and in vivo in rats, dogs and humans.


RWJ-51204 anxiolytic agent in vitro & in vivo metabolism animals human ms & ms/ms metabolite identification 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    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, Gardocki, J.F., (1995): Potential anxiolytic agents, pyrido[l,2-a]benzimidazole: anew structural class of ligands for the benzodiazepine binding site on GABA-A receptors, J. Med. Chem., 38,16–20.CrossRefPubMedGoogle Scholar
  2. 2.
    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[l,2-a]benzimidazole (PBI) class of GABA-A receptor modulators, Bioorg. Med. Chem. Lett., 6, 333–338.CrossRefGoogle Scholar
  3. 3.
    Reitz, A.B., Jordan, A.D., Sanfilippo, P.J., and Vavouyios-Smith, A., ( 1998): US Patent, 5,817,668,6.Google Scholar
  4. 4.
    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-a]benzimidazole, Bioorg. Med. Chem. Lett., 9 1547–1552.CrossRefPubMedGoogle Scholar
  5. 5.
    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.CrossRefPubMedGoogle Scholar
  6. 6.
    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-a]benzimidazoles with high GABA-A receptor affinity, Bioorg. Med. Chem. Lett.,12,2381–2386.CrossRefPubMedGoogle Scholar
  7. 7.
    Dubinsky, B., Vaidya, A.H., Rosenthal, D.I., Hochman, C., Crooke, J.J., Deluca, S., Devine, A., Cheo-Isaacs, C.T., Carter, A.R., Jordan, A.D., Reitz, A.B. and Shank, R.P., (2002): 5-Ethoxymethyl-7-fluoro-3-oxo-l,2,3,5-tetrahydrobenzo[4,5]imidazo [l,2a]pyridine-4-N-(2-fluorophenyl)carboxamide (RWJ-51204), a new nonbenzodiazepine anxiolytic, J. Pharmacol. Exp. Ther., 303,777–790.CrossRefPubMedGoogle Scholar
  8. 8.
    Wu, W.N., McKown, L.A., Reitz, A.B., andTakacs, A.R., (1998): In vitro metabolism of the anxiolytic agent, RWJ-51204, in mouse, rat, dog, monkey and human hepatic S9. The AAPS Annual Meeting and Exposition, Abstract no. 1167, Pharm. Sei., 1, PS36.Google Scholar
  9. 9.
    Wu, W.N., and McKown, L.A., (1999): In vivo metabolism of anxiolytic agent, RWJ-51204, in the rat and dog, The 9th N. Amer. ISSX/ACS-DCT Meeting, Abstract no. 34, ISSX Proceedings, 15,174.Google Scholar
  10. 10.
    Wu, W.N., McKown, L.A., and Reitz, A.B., (2002): Metabolism of the anxiolytic agent, RWJ-51204, in human (2.5 mg/subject single oral dose), catalyzed by CYP3A4 isoform, The 11th N. Amer. ISSX Meeting, Abstract no. 163, Drug Metab. Rev., 34,82.Google Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • W. N. Wu
    • 1
  • L. A. McKown
    • 1
  • A. B. Reitz
    • 1
  1. 1.Johnson & Johnson Pharmaceutical Research & DevelopmentL.L.C.Spring HouseUSA

Personalised recommendations