Stereoselective Disposition of Pranoprofen, a Nonsteroidal Antiinflammatory Drug, in Rabbits

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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. The glucuronidation of R(-)-isomer was 4-fold faster than S(+)-isomer in the kidney, although the hydrolysis from glucuronide to pranoprofen in the kidney was faster for R(-)-isomer than S(+)-isomer. It was concluded from the present limited data that conjugation of the R(-)-isomer depended predominantly upon its higher free plasma level and higher metabolic rate and it thus was rapidly excreted from the kidney. This describes the stereoselectivity in the elimination process of pranoprofen which might be responsible for a significant difference in plasma concentration between S(+)- and R(-)-pranoprofen.
公益社団法人日本薬学会の論文
1993-03-15

Stereoselective Disposition of Pranoprofen, a Nonsteroidal Antiinflammatory Drug, in Rabbits

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