Skip to main content
SpringerLink
Log in

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

  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Summary

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 systme, 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Carson, J. R., Carmosin, R. J., Pitis, P. M., Vaught, J. L., Almond, H. R., Stables, J. P., Wolf, H. H., Swinyard, and White, H. S., (1997): Aroyl(aminoacyl)pyrroles, a new class of anticonvulsant agents. J. Med. Chem., 40(11), 1578–1584.

    Article  CAS  PubMed  Google Scholar 

  2. Carmosin, R. J., Carson, J. R., and Pitis, P. M., (1994): Preparation of anticonvulsant aroyl(aminoacyl)pyrroles, US Patent No. 5332736.

  3. Carson, J. R., Pitis, P. M., and Rogers, K. E., (2000): preparation of aminoacyl(aroyl)pyrroles for treatment of neuropathic pain, US Patent No. 99120477.

  4. Estrada, E., and Pena, A., (2000): In silico studies for the rational discovery of anticonvulsant compounds. Bioorg. Med. Chem., 8(12), 2755–2770.

    Article  CAS  PubMed  Google Scholar 

  5. Chong, M. S., and Smith, T. E., (2000): Anticonvulsants for the management of pain. Pain Reviews, 7, 129–149.

    CAS  Google Scholar 

  6. Sumner, D. D., Dayton, P. G., Cucinell, S. A., and Plostnieks, J. (1975): Metabolism of tolmetin in rat, monkey, and man, Drug Metabolism and Disposition, 3(4): 283–286.

    CAS  PubMed  Google Scholar 

  7. Grindell, J. M., O’Neill, P. J., Yorgey, K. A., Schwartz, M. H., McKown, L. A., Migdalof, B. H., and Wu, W. N., (1980): The metabolism of zomepira. I. Disposition in laboratory animals and man. Drug Metabolism and Disposition, 8(3), 343–348.

    Google Scholar 

  8. Wu, W. N., Weaner, L. E., Kalbron, J., O’Neill, P. J., and Grindell, J. M., (1980): The metabolism of zomepirac sodium II. Isolation and identification of the urinary metabolites in rat, mouse, rhesus monkey, and human. Drug Metabolism and Disposition, 8(3), 349–352.

    CAS  PubMed  Google Scholar 

  9. Hasegawa, J., Smith, P. C., and Benet, L. Z. (1982): Apparent intramolecular acyl migration of zomepirac glucuronide. Drug Metabolism and Disposition, 10(5), 469–473.

    CAS  PubMed  Google Scholar 

  10. Wu, W. N., McKown, L. A., and J. R. Carson, (2000): In vitro metabolism of the analgesic agent, RWJ-37874, in rat and human hepatic S9 fractions (Abstract # 195. The 13th International Symposium on Microsomes and Drug Oxidation).

Download references

Author information

Authors and Affiliations

  1. Division of Preclinical Drug Evaluation, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., McKean & Welsh Roads, 19477, Spring House, PA, USA

    W. N. Wu & L. A. McKown

  2. Division of Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., McKean & Welsh Roads, 19477, Spring House, PA, USA

    J. R. Carson

Authors
  1. W. N. Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. A. McKown
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. R. Carson
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, W.N., McKown, L.A. & Carson, J.R. In Vitro metabolism of the analgesic agent, RWJ-37874, in rat and human. Eur. J. Drug Metab. Pharmacokinet. 28, 101–105 (2003). https://doi.org/10.1007/BF03190496

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03190496

Keywords

Search

Navigation