Involvement of the rat gut epithelial and muscular layer, and microflora in chiral inversion and acyl-glucuronidation of R-fenoprofen.
In the presence of excised human and rat gut, the pharmacologically inactive R enantiomers of both ibuprofen and fenoprofen (FN) are bioinverted to their anti-inflammatory antipodes. In an attempt to further localize the site of inversion, we incubated R-FN, in oxygenated (O2:CO2, 95:5, v/v) Krebs-Henseleit solution (37 degrees C, pH 7.4) for 3 h in the presence of the intestinal contents, epithelium and muscular layer of upper jejunum and everted jejunum sack of antibiotic treated (500 mg/kg neomycin and erythromycin b.i.d. for 3 days) and control adult female Sprague-Dawley rats. The formation of S-FN and acylglucuronidated FN was examined in the incubation medium using a stereospecific HPLC assay. The metabolic activities are reported per g of wet tissue. The extent of inversion by the everted rat gut was substantial (30.7 +/- 5.1%) but no significant differences between the control and germ-eradicated rats was observed. The epithelial cells were found to be the major site of inversion in the intestinal wall (37.5 +/- 4.7%) with the muscular layer (7.8 +/- 2.1%) and intestinal contents (5.7 +/- 2.2%) contributing only to a small extent to the process. Both enantiomers were substantially acyl-glucuconjugated in the epithelial and muscular layers, and the intestinal content.
Sattari
S
S
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Jamali
F
F
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism* / Q000493:pharmacokinetics; D001711:Biotransformation; D004848:Epithelium / Q000378:metabolism; D005260:Female; D005279:Fenoprofen / Q000378:metabolism* / Q000493:pharmacokinetics; D005965:Glucuronates / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000382:microbiology*; D007583:Jejunum / Q000378:metabolism / Q000382:microbiology; D009130:Muscle, Smooth / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005965:Glucuronates; D005279:Fenoprofen