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Mechanistic studies on the metabolic chiral inversion of R-ibuprofen in the rat.
Drug Metab Dispos. 1991 Mar-Apr; 19(2):405-10.DM

Abstract

Deuterium labeling techniques and stereoselective GC/MS methodology have been employed to investigate the mechanism by which R-ibuprofen undergoes metabolic chiral inversion in the rat in vivo. Following oral administration of a mixture of R-ibuprofen (7.5 mg kg-1) and R-[ring-2H4; 2-2H]ibuprofen (R-[2H5]ibuprofen) (7.5 mg kg-1) to male Sprague-Dawley rats, the enantiomeric composition and deuterium excess of the drug were determined in serial plasma samples and in pooled urine collected over 10 hr. The results demonstrate that: (i) R-ibuprofen undergoes extensive inversion of configuration to its S antipode in the rat; (ii) chiral inversion of R-[2H5]ibuprofen yields S-[2H4]ibuprofen in a process that involves quantitative loss of the deuterium atom present originally at C-2; (iii) labeling of R-ibuprofen with deuterium at C-2 does not introduce a measurable kinetic deuterium isotope effect on the chiral inversion reaction; and (iv) metabolism of R-[2H5]ibuprofen leads to the appearance in plasma and urine of molecules of R-ibuprofen labeled with 4 atoms of deuterium. On the basis of these findings, a mechanism is proposed for the chiral inversion reaction that invokes the stereoselective formation of the coenzyme A thioester of R-ibuprofen as a key metabolite; conversion of this species to the corresponding enolate tautomer affords a symmetrical intermediate through which racemization of ibuprofen occurs in vivo.

Authors+Show Affiliations

Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

1676645

Citation

Sanins, S M., et al. "Mechanistic Studies On the Metabolic Chiral Inversion of R-ibuprofen in the Rat." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 19, no. 2, 1991, pp. 405-10.
Sanins SM, Adams WJ, Kaiser DG, et al. Mechanistic studies on the metabolic chiral inversion of R-ibuprofen in the rat. Drug Metab Dispos. 1991;19(2):405-10.
Sanins, S. M., Adams, W. J., Kaiser, D. G., Halstead, G. W., Hosley, J., Barnes, H., & Baillie, T. A. (1991). Mechanistic studies on the metabolic chiral inversion of R-ibuprofen in the rat. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 19(2), 405-10.
Sanins SM, et al. Mechanistic Studies On the Metabolic Chiral Inversion of R-ibuprofen in the Rat. Drug Metab Dispos. 1991 Mar-Apr;19(2):405-10. PubMed PMID: 1676645.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanistic studies on the metabolic chiral inversion of R-ibuprofen in the rat. AU - Sanins,S M, AU - Adams,W J, AU - Kaiser,D G, AU - Halstead,G W, AU - Hosley,J, AU - Barnes,H, AU - Baillie,T A, PY - 1991/3/1/pubmed PY - 1991/3/1/medline PY - 1991/3/1/entrez SP - 405 EP - 10 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 19 IS - 2 N2 - Deuterium labeling techniques and stereoselective GC/MS methodology have been employed to investigate the mechanism by which R-ibuprofen undergoes metabolic chiral inversion in the rat in vivo. Following oral administration of a mixture of R-ibuprofen (7.5 mg kg-1) and R-[ring-2H4; 2-2H]ibuprofen (R-[2H5]ibuprofen) (7.5 mg kg-1) to male Sprague-Dawley rats, the enantiomeric composition and deuterium excess of the drug were determined in serial plasma samples and in pooled urine collected over 10 hr. The results demonstrate that: (i) R-ibuprofen undergoes extensive inversion of configuration to its S antipode in the rat; (ii) chiral inversion of R-[2H5]ibuprofen yields S-[2H4]ibuprofen in a process that involves quantitative loss of the deuterium atom present originally at C-2; (iii) labeling of R-ibuprofen with deuterium at C-2 does not introduce a measurable kinetic deuterium isotope effect on the chiral inversion reaction; and (iv) metabolism of R-[2H5]ibuprofen leads to the appearance in plasma and urine of molecules of R-ibuprofen labeled with 4 atoms of deuterium. On the basis of these findings, a mechanism is proposed for the chiral inversion reaction that invokes the stereoselective formation of the coenzyme A thioester of R-ibuprofen as a key metabolite; conversion of this species to the corresponding enolate tautomer affords a symmetrical intermediate through which racemization of ibuprofen occurs in vivo. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/1676645/Mechanistic_studies_on_the_metabolic_chiral_inversion_of_R_ibuprofen_in_the_rat_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=1676645 DB - PRIME DP - Unbound Medicine ER -