Presystemic and systemic chiral inversion of R-(-)-fenoprofen in the rat.
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.
Berry
B W
BW
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Jamali
F
F
D000818:Animals; D005279:Fenoprofen / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism; D007052:Ibuprofen / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D005965:Glucuronates; D005279:Fenoprofen; D007052:Ibuprofen