Stereoselective disposition of carvedilol is determined by CYP2D6*

Abstract

Carvedilol is a mixed alpha- and beta-adrenergic receptor antagonist that is administered as a racemic mixture. Although the two isomers are equally potent as alpha 1-blockers the S(-)-isomer is principally responsible for the beta blockade of carvedilol. To determine the role of pharmacogenetics in the metabolism of carvedilol we studied nine extensive metabolizers of both debrisoquin and mephenytoin, seven poor metabolizers of debrisoquin but extensive metabolizers of mephenytoin, and three poor metabolizers of mephenytoin but extensive metabolizers of debrisoquin. The clearance of R-carvedilol was significantly lower than S-carvedilol in both debrisoquin phenotypes. Poor metabolizers of debrisoquin had a significantly lower clearance of R-carvedilol than extensive metabolizers of debrisoquin. The partial metabolic clearance of carvedilol to the two ring-hydroxylated metabolites 4- and 5-hydroxyphenyl carvedilol were significantly reduced in poor metabolizers of debrisoquin. No effect of mephenytoin phenotype on carvedilol kinetics was observed. Thus carvedilol is stereoselectively metabolized in humans, and the clearance of S-carvedilol is higher than that of R-carvedilol. In poor metabolizers of debrisoquin the clearance of R-carvedilol is further reduced, resulting in higher plasma concentrations and perhaps greater alpha-blockade.

The clinical role of genetic polymorphisms in drug-metabolizing enzymes

“…PMs demonstrated an impaired clearance of R-carvedilol, thus being affected by a more pronounced a1-blockade which might outweigh the beneficial b1-blocking effects. 47 Hence, CYP2D6 genotyping might predict therapeutic outcome in patients with chronic heart failure treated with carvedilol. However, the inhibition of CYP2D6 metabolism by administration of fluoxetine in EMs led to significant changes in plasma pharmacokinetics in favor of the R-enantiomer without any effects on blood pressure and heart rate which casts doubt on the clinical significance of the CYP2D6 genotype for the treatment with carvedilol in antihypertensive therapy.…”

The relationship between plasma concentration of metoprolol and CYP2D6 genotype in patients with ischemic heart disease

“…Zhou and Wood showed that the clearance of the carvedilol R-enantiomer (+) was 66% lower among poor metabolizers compared to EMs. The researchers also demonstrated that in PMs the area under the curve (AUC) increased by 138% [9].…”

Anestesia na população negra

“…A diminuição anormal da calicreína urinária no negro hipertenso torna-o mais sensível ao aumento de bradicinina induzido pelo IECA: a diminuição da angiotensina II se acompanha do aumento da bradicinina (menor degradação), o que torna mais freqüente ocorrência de tosse e os episódios de angioedema 52,53 . O hipertenso com insuficiência cardíaca de diferentes raças responde favoravelmente à administração do bloqueador α e β como o carvedilol, podendo ser associado ou não a antagonistas de canais lentos de cálcio ou a uma terapêutica diuréti-ca 3, 54,55 . O alelo polimorfo T do gen C825T do unidade β 3 da proteína G facilita a excreção renal de Na + /H + em resposta à manoterapia com diurético benzotiazídico em negros hipertensos com baixo nível de renina 38,39 .…”