Abstract
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 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 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.
Footnotes
-
Send reprint requests to: Prof. Roger K. Verbeeck, UCL/FATC 7355, School of Pharmacy, Av. E. Mounier 73, B-1200 Brussels, Belgium.
- Received July 17, 1996.
- Accepted January 14, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|