Biliary excretion and enterohepatic cycling of R- and S-flurbiprofen in the rat.

According to a previously published report, R- and S-flurbiprofen glucuronides were excreted in the bile after iv administration of the pure enantiomers, but only R-flurbiprofen seemed to undergo enterophepatic 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 administration 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 with S-FL (CL: 0.72 +/- 0.10 ml.min-1.kg-1, Vd:312 +/- 12 ml.kg-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 administered 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.min-1.kg-1 in control rats, p < 0.05), whereas CL of R-FL was not affected. Paired rat experiments in which the 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 administration of 20 mg.kg-1 R, S-FL to the donor rat. Our results clearly show that R- and S-FL glucuronides are excreted via the bile and subsequently undergo hydrolysis followed by reabsorption of both R- and S-FL