Stereoselective Effect of Amiodarone on the Pharmacokinetics of Racemic Carvedilol

We investigated whether there was a stereoselective effect of amiodarone on the pharmacokinetics of carvedilol. Among a series of 106 inpatients with heart failure, 52 received carvedilol monotherapy (carvedilol group) and 54 received carvedilol plus amiodarone (carvedilol + amiodarone group). The serum carvedilol concentration administered /dose ratio was compared between the two groups based on HPLC measurement of the serum levels of carvedilol, amiodarone, and desethylamiodarone. In 6 patients from the carvedilol group, serum carvedilol levels were compared before and after coadministration of amiodarone. There was no significant between-group difference of the serum concentration to dose (C /D ratio) for the R-enantiomer carvedilol, however, the C/D ratio for the S-enantiomer and the serum S-carvedilol to R-carvedilol (S/R) ratio were both significantly lower in the carvedilol group than in the carvedilol + amiodarone group(47.8±56.7 versus 95.3±105ng/mg/kg, P = 0.0048 and 0.460 ± 0.207 versus 0.879 ± 0.377 ng/mg/kg, P < 0.001), respectively. Furthermore, the mean S-carvedilol concentration over 14 days of coadministration with amiodarone was higher than that before coadministration (6.54 ± 1.73 ng/mL versus 3.03±0.670ng/mL, P<0.001). These results suggest that metabolism of S-carvedilol was markedly inhibited by coadministration of amiodarone.