BILIARY-EXCRETION AND ENTEROHEPATIC CYCLING OF R-FLURBIPROFEN AND S-FLURBIPROFEN IN THE RAT

According to a previously published report, R- and S-flurbiprofen gluc uronides were excreted in the bile after iv administration of the pure enantiomers, but only R-flurbiprofen seemed to undergo enterohepatic cycling. To study the possible stereospecificity in the enterohepatic cycling of flurbiprofen (FL), we investigated the pharmacokinetics of R- and S-FL in control and bile-duct cannulated rats after iv administ ration of racemic FL (20 mg . kg(-1)). FL pharmacokinetics were highly stereospecific in control rats: plasma clearance (CL) was much higher and distribution volume (Vd) larger for R-FL (2.60 +/- 0.51 ml . min( -1) . kg(-1) and 500 +/- 59 ml . kg(-1), respectively) as compared wit h S-FL (CL: 0.72 +/- 0.10 ml . min(-1) . kg(-1), Vd: 312 +/- 12 ml . k g(-1)). Renal excretion of the R- and S-FL glucuronides was extremely small (< 0.5%), whereas biliary excretion accounted for 8.3 +/- 1.8% ( R-FL glucuronide) and 14.3 +/- 2.4% (S-FL glucuronide) of the administ ered dose. Bile-duct cannulation significantly increased CL of S-FL (0 .90 +/- 0.10 ml . min(-1) . kg(-1) compared with 0.72 +/- 0.10 ml . mi n(-1) . kg(-1) in control rats, p < 0.05), whereas CL of R-FL was not affected, Paired rat experiments in which;he bile of the first rat was deviated into the duodenum of the second rat demonstrated measurable plasma concentrations of R- and S-FL in the receiver rat after iv admi nistration of 20 mg . kg(-1) R, S-FL to the donor rat. Our results cle arly show that R- and S-FL glucuronides are excreted via the bile and subsequently undergo hydrolysis followed by reabsorption of both R- an d S-FL.