Effects of CYP2D6*10 and CYP2D6*5 alleles on the pharmacokinetics of carvedilol in healthy Koreans

Purpose: Carvedilol is a non-selective α- and β-adrenergic receptor blocking agent, which is indicated for the treatment of hypertension, chronic heart failure, and left ventricular dysfunction following myocardial infarction. CYP2D6 is the major enzyme that mediates the metabolism of carvedilol via 4’-hydroxylation and 5’-hydroxylation. Among over 100 alleles in CYP2D6 gene, CYP2D6*2, *5, *10, and CYP2D6 gene duplication/multiplication (*XN) are functionally important in Asians, including Koreans. We investigated the effects of CYP2D6*10 and CYP2D6*5 alleles on the pharmacokinetics of carvedilol.

Methods: Thirty-four healthy subjects were selected and they were divided into three different groups according to CYP2D6 genotype, group1 (CYP2D6*1/*1, n=8), group2 (CYP2D6*1/*5 and CYP2D6*1/*10, n=15) and group3 (CYP2D6*5/*10 and CYP2D6*10/*10, n=11). After overnight fasting, each subject received a single oral dose of 25 mg carvedilol. Blood samples were collected up to 12 hr after drug intake, and the plasma concentrations of carvedilol were determined by using HPLC system with fluorescence detection.

Results: AUC_inf of carvedilol in group3 was 270.2 ± 110.4 ng·hr/mL, that is 2.0- and 1.6-fold higher than that in group1 and group2 (137.9 ± 66.3 ng·hr/mL and 168.5 ± 70.2 ng·hr/mL, respectively, P<0.01). C_max of carvedilol in group3 (54.0 ± 24.0 ng/mL) was also 1.7- and 1.3-fold higher than that in group1 and group2 (32.0 ± 13.0 ng/mL and 43.0 ± 20.5 ng/mL, respectively), but these differences were not statistically significant.

Conclusion: CYP2D6*10 and CYP2D6*5 alleles significantly affect the pharmacokinetics of carvedilol.