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Presystemic and systemic chiral inversion of R-(-)-fenoprofen in the rat.
J Pharmacol Exp Ther. 1991 Aug; 258(2):695-701.JP

Abstract

Fenoprofen (FN), a member of the 2-arylpropionic acid (2-APA) class of nonsteroidal anti-inflammatory drugs is administered clinically as a racemate. In humans, FN has been shown to rapidly undergo substantial in vivo unidirectional chiral inversion with the inactive R-isomer converted to its active antipode. As with any p.o. administered drug, before reaching the systemic circulation. FN may undergo first-pass metabolism, the major organs involved being the gastrointestinal tract and/or the liver. The site(s) of inversion for the 2-APAs have been a subject of debate, with presystemic intestinal metabolism in humans and hepatic systemic metabolism in rats receiving the most attention. The inversion of R-FN was studied in the male Sprague-Dawley rat 1) in vivo after p.o. and i.v. administration of racemic-FN and R-FN, 2) after perfusion of R-FN into isolated liver (single-pass and recirculation) and 3) after a 2-hr incubation with everted intestinal tissue (duodenum, jejunum, ileum and colon) and noneverted stomach pouch. The enantiomers and their acyl-glucuronides were quantitated using a previously developed stereospecific assay. With the isolated liver, R-FN was shown to invert in both the single-pass and recirculation systems, with a first-pass extraction ratio of 0.3. A significant but variable inversion in all intestinal segments was observed. Substantial inversion by the duodenum was observed (serosal S:R ratio, 1.2) with maximal inversion by the jejunum (serosal S:R ratio, 2.2), whereas inversion of R-FN was absent in the stomach. Considerable glucuronidation was observed in all tissues studied including first-pass glucuronidation of both enantiomers after single-pass perfusion through the isolated liver and stereoselective glucuronidation in intestinal tissue segments. The results indicate that, in the male Sprague-Dawley rat, R-FN undergoes presystemic inversion by both the gastrointestinal tract and liver. These results, however, must be viewed with caution as they may not necessarily be extrapolated to other 2-APAs or species.

Authors+Show Affiliations

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.No affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

1865366

Citation

Berry, B W., and F Jamali. "Presystemic and Systemic Chiral Inversion of R-(-)-fenoprofen in the Rat." The Journal of Pharmacology and Experimental Therapeutics, vol. 258, no. 2, 1991, pp. 695-701.
Berry BW, Jamali F. Presystemic and systemic chiral inversion of R-(-)-fenoprofen in the rat. J Pharmacol Exp Ther. 1991;258(2):695-701.
Berry, B. W., & Jamali, F. (1991). Presystemic and systemic chiral inversion of R-(-)-fenoprofen in the rat. The Journal of Pharmacology and Experimental Therapeutics, 258(2), 695-701.
Berry BW, Jamali F. Presystemic and Systemic Chiral Inversion of R-(-)-fenoprofen in the Rat. J Pharmacol Exp Ther. 1991;258(2):695-701. PubMed PMID: 1865366.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Presystemic and systemic chiral inversion of R-(-)-fenoprofen in the rat. AU - Berry,B W, AU - Jamali,F, PY - 1991/8/1/pubmed PY - 1991/8/1/medline PY - 1991/8/1/entrez SP - 695 EP - 701 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 258 IS - 2 N2 - Fenoprofen (FN), a member of the 2-arylpropionic acid (2-APA) class of nonsteroidal anti-inflammatory drugs is administered clinically as a racemate. In humans, FN has been shown to rapidly undergo substantial in vivo unidirectional chiral inversion with the inactive R-isomer converted to its active antipode. As with any p.o. administered drug, before reaching the systemic circulation. FN may undergo first-pass metabolism, the major organs involved being the gastrointestinal tract and/or the liver. The site(s) of inversion for the 2-APAs have been a subject of debate, with presystemic intestinal metabolism in humans and hepatic systemic metabolism in rats receiving the most attention. The inversion of R-FN was studied in the male Sprague-Dawley rat 1) in vivo after p.o. and i.v. administration of racemic-FN and R-FN, 2) after perfusion of R-FN into isolated liver (single-pass and recirculation) and 3) after a 2-hr incubation with everted intestinal tissue (duodenum, jejunum, ileum and colon) and noneverted stomach pouch. The enantiomers and their acyl-glucuronides were quantitated using a previously developed stereospecific assay. With the isolated liver, R-FN was shown to invert in both the single-pass and recirculation systems, with a first-pass extraction ratio of 0.3. A significant but variable inversion in all intestinal segments was observed. Substantial inversion by the duodenum was observed (serosal S:R ratio, 1.2) with maximal inversion by the jejunum (serosal S:R ratio, 2.2), whereas inversion of R-FN was absent in the stomach. Considerable glucuronidation was observed in all tissues studied including first-pass glucuronidation of both enantiomers after single-pass perfusion through the isolated liver and stereoselective glucuronidation in intestinal tissue segments. The results indicate that, in the male Sprague-Dawley rat, R-FN undergoes presystemic inversion by both the gastrointestinal tract and liver. These results, however, must be viewed with caution as they may not necessarily be extrapolated to other 2-APAs or species. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/1865366/Presystemic_and_systemic_chiral_inversion_of_R_____fenoprofen_in_the_rat_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=1865366 DB - PRIME DP - Unbound Medicine ER -