Stereoselective pharmacokinetics of flurbiprofen in humans and rats

Abstract

Flurbiprofen, a 2-arylpropionic acid (2-APA) nonsteroidal anti-inflammatory drug (NSAID), exists as racemate and is used as such. Although the activity of 2-APAs is due mainly to their S-enantiomers, information on the pharmacokinetics of flurbiprofen is usually based on the measurement of total concentrations of S- and R-flurbiprofen. In this work, the pharmacokinetics of flurbiprofen enantiomers following single doses were studied in humans and rats. Upon iv administration of 10 mg/kg of racemic flurbiprofen to male Sprague-Dawley rats, the plasma concentrations were consistently higher for S-flurbiprofen than for R-flurbiprofen (AUC = 134 +/- 39 versus 41 +/- 9 mg.L-1 h). In bile duct-cannulated rats, the biliary excretion contained only 3.6-5.2% of the dose as conjugated flurbiprofen (S:R = 1.2-2.1). After administration of R-flurbiprofen to the rat, both enantiomers were found in plasma [AUC(R):AUC(S) = 0.10-0.16], indicating a limited extent of enantiomeric bioinversion. This is consistent with the previously reported limited extent of flurbiprofen uptake into fat. In healthy volunteers also, significant stereoselectivity was observed in the plasma concentration of the drug after 100-mg oral racemic doses [AUC-(S):AUC(R) = 45.4 +/- 12.7:40.1 +/- 14.3 mg.L-1.h]. As compared with the R-enantiomer, S-flurbiprofen has a smaller volume of distribution (7.23 +/- 1.9 versus 8.41 +/- 3.0 L) and total clearance (1.23 +/- 0.34 versus 1.47 +/- 0.50 L/h), but an equal half-life (4.21 +/- 1.2 versus 4.18 +/- 1.3 h). In urine, on the other hand, the R-configuration was predominant, as greater amounts of the R-enantiomer were found both as conjugated flurbiprofen and as an unidentified metabolite. Negligible amounts of intact flurbiprofen enantiomers were detected in urine. The observed stereoselectivity in humans cannot be attributed to enantiomeric bioinversion, as S-flurbiprofen was not detected in plasma and urine after oral administration of R-flurbiprofen.