Disposition of carvedilol enantiomers in patients with liver cirrhosis: evidence for disappearance of stereoselective first-pass extraction.
The racemic drug carvedilol exerts its antihypertensive action through vasodilation and nonselective beta-blockade. The R(+)-enantiomer has twice (31.1%) the absolute bioavailability than the S(-) form (15.1%). The pharmacokinetics of the enantiomers were investigated after intravenous (i.v.) (12.5 mg in 1 h) and p.o. (25 mg) administration of racemic carvedilol in six patients with cirrhosis of the liver according to a randomized crossover design. Although the difference between areas under the curve of R(+) and S(-) were of borderline significance after i.v. administration but significant after oral administration, no difference existed between the absolute bioavailabilities of R(+) (83.7%) and S(-) (71.3%). The enantiomer ratio is similar after i.v. (1.3) and p.o. administration (1.6). In contrast to healthy subjects, the apparent volume of distribution of S(-) is about 90% greater than that of R(+) in patients. The renal excretion of carvedilol and of one of its major metabolites, carvedilol glucuronide, also exhibited stereoselective behavior, but in opposite directions. In patients with liver cirrhosis, stereoselective metabolism of carvedilol is still operative. However, probably because of portocaval shunts, the hepatic first-pass extraction is markedly reduced, eliminating the difference in bioavailability between the two enantiomers.
Neugebauer
G
G
Department of Clinical Pharmacology, Boehringer Mannheim GmbH, Germany.
Gabor
M
M
Reiff
K
K
D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D000328:Adult; D000368:Aged; D001682:Biological Availability; D002227:Carbazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000077261:Carvedilol; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011412:Propanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011897:Random Allocation; D013237:Stereoisomerism; D014018:Tissue Distribution; D014665:Vasodilator Agents / Q000493:pharmacokinetics*
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D014665:Vasodilator Agents; D000077261:Carvedilol