Stereoselective disposition of carvedilol in man after intravenous and oral administration of the racemic compound

Abstract

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-beta-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.

The clinical role of genetic polymorphisms in drug-metabolizing enzymes

“…45 Whereas b1-antagonism is primarily conferred by the S-enantiomer of carvedilol, the R-isoform is responsible for a1-blockade.…”

Crystalline and amorphous carvedilol-loaded nanoemulsions: formulation optimisation using response surface methodology

“…Its solubility values are 51 mg mL À1 above pH 9.0, 23 mg mL À1 at pH 7 and about 100 mg mL À1 at pH 5 at room temperature [19]. Carvedilol undergoes significant stereoselective first-pass metabolism, resulting in low absolute bioavailability (30% or less) [20][21][22]. However, some sources suggest that this low bioavailability is the result of poor aqueous solubility [21,23].…”

Population Pharmacokinetics of R- and S-Carvedilol in Japanese Patients with Chronic Heart Failure

“…9) Absolute bioavailability upon oral administration is 31.1% and 15.1% for the R-and Senantiomers, respectively, and the difference in metabolic stability is attributed mainly to CYP2D6. 10,11) Carvedilol shows high plasma protein binding (98-99%), 12) and is known to bind to a 1 -acid glycoprotein with high affinity. 13) The COMMET study reported that serious adverse and CHF-related events in patients switching from metoprolol (a b 1 -selective agent) to carvedilol (a nonselective agent) were lower than in patients switching from carvedilol to metoprolol.…”