Pharmacokinetics of propafenone enantiomers in rats

R Mehvar

Drake University, College of Pharmacy and Health Sciences, Des Moines, IA 50311.

Pharmacokinetics of propafenone (PPF) enantiomers were investigated in adult male Sprague-Dawley rats after iv, po, and ip administration of a single 10 mg/kg dose of the racemate. After all routes of administration, the AUC for the (-)-enantiomer was significantly higher than that of its antipode: the mean +/- SD values of (-):(+) AUC ratio were 1.99 +/- 0.228, 2.52 +/- 0.525, and 3.54 +/- 1.12 for the iv, ip, and po data, respectively. The respective absolute bioavailabilities of the (-)- and (+)-enantiomers were 0.422 and 0.254 after po administration and 0.493 and 0.402 after ip administration, indicating stereoselectivity in the first-pass metabolism of the drug. Only negligible amounts of the enantiomers were excreted unchanged into the urine of rats, suggesting that elimination of PPF in rats, as in humans, is almost entirely dependent on its metabolism. Compared with the iv and ip data, serum concentrations of the enantiomers after po administration remained above the assay sensitivity for a longer period of time. This was due to the presence of multiple peaks in the serum concentration-time courses of the enantiomers after po administration. In an exploratory experiment, it was shown that co-administration of quinidine sulfate drastically increases serum concentrations of both PPF enantiomers. The results of our study indicate that, in rats, pharmacokinetics of PPF are stereoselective and that the route of administration affects the degree of this stereoselectivity.

Volume 18, Issue 6, pp. 987-991, 11/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics