STEREOSELECTIVE DISPOSITION OF CARVEDILOL IN MAN AFTER INTRAVENOUS AND ORAL-ADMINISTRATION OF THE RACEMIC COMPOUND

The racemic compound carvedilol is a multiple-action oral antihypertensive drug that exhibits both vasodilator and non-selective beta-adrenergic blocking activities. The effects of the levorotatory S-enantiomer [S( - )-CARV] are vasodilatation and beta-blockade. The R (+)-enantiomer [R (+)-CARV] is a pure vasodilating agent. Quantitative determination of the enantiomers in human plasma by HPLC was carried out after formation of diastereoisomers with the chiral reagent 2,3,4,6-tetra O-acetyl-β-d-glucopyranosyl isothiocyanate (GITC). The pharmacokinetics of the enantiomers were studied following i. v. (12.5 mg in 1 h) and p. o. (50 mg) administration of racemic carvedilol in ten healthy male subjects according to a randomized crossover design. The AUCs of S (-)-CARV were significantly lower than those of R (+)-CARV after both i. v. and p. o. administration. The systemic clearance of the two enantiomers was significantly different, whereas half-lives and apparent distribution volumes were comparable. Following p. o. administration, the absolute bioavailability (31.1% and 15.1%, respectively) and maximal plasma concentrations of R (+ )-CARV were twice those of S (-)-CARV A similar difference was found in the half-lives. A close correlation existed between enantiomeric ratios after i.v. and after p. o. administration, demonstrating slight intraindividual variability. The preferential systemic clearance of the S ( - )-enantiomer suggests stereoselective hepatic metabolism of carvedilol, becoming especially apparent after p. o. administration. The small intrasubject variability in enantiomer ratios indicates a relatively constant relation of beta-blockade to vasodilation during chronic treatment. © 1990 Springer-Verlag.