Stereoselective disposition of pranoprofen, a nonsteroidal antiinflammatory drug, in rabbits.
The stereoselective disposition of pranoprofen, a nonsteroidal antiinflammatory drug, was studied in rabbits. Plasma levels of S(+)-pranoprofen after oral and i.v. administration of the racemate pranoprofen were always higher than those of the R(-)-isomer. The elimination rate constant of the R(-)-isomer (2.74 h-1), calculated using a 2-compartment model, was significantly larger than that of the S(+)-isomer (2.14 h-1), while no significant difference was observed in the absorption rate constants between enantiomers. Pranoprofen was excreted in the urine exclusively in the form of pranoprofen glucuronide. The glucuronide of R(-)-isomer was excreted more rapidly than the S(+)-isomer. However, no metabolite of pranoprofen was detected in plasma, owing to its instability in liver and plasma. Moreover, the elimination of the S(+)- and R(-)-isomers of pranoprofen was more rapid when the enantiomers were separately administered than when administered as the racemate. The R(-)-isomer showed a significantly higher elimination rate than the S(+)-isomer, compared to what was observed upon the administration of the racemate. No inversion to an R(-)-form or S(+)-form to their corresponding antipode after administration of the isomers separately was detected. Pranoprofen, especially the R(-)-isomer, was significantly distributed in the kidney. An in vitro metabolism experiment of pranoprofen showed the predominant glucuronidation to be in the kidney rather than in the liver because of rapid hydrolysis of glucuronide in the liver.(ABSTRACT TRUNCATED AT 250 WORDS)
Nomura
T
T
Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
Imai
T
T
Otagiri
M
M
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics*; D001578:Benzopyrans / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D005965:Glucuronates / Q000378:metabolism; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008297:Male; D011422:Propionates / Q000097:blood / Q000493:pharmacokinetics*; D011485:Protein Binding; D011817:Rabbits; D013237:Stereoisomerism; D014018:Tissue Distribution
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D005965:Glucuronates; D011422:Propionates; C043940:pyranoprofen