Key result
Amiodarone and desethylamiodarone significantly decreased the oxidation of R- and S-carvedilol, while increasing the glucuronidation of R-carvedilol by 1.6- and 1.4-fold, respectively.
Why the study?
Does amiodarone or desethylamiodarone alter the oxidation and glucuronidation of R- and S-carvedilol in human liver microsomes?
Does amiodarone or desethylamiodarone alter the oxidation and glucuronidation of R- and S-carvedilol in human liver microsomes?
The study provides a mechanistic explanation for the increased serum concentration of S-carvedilol when coadministered with amiodarone, driven by inhibition of S-carvedilol oxidation.
May suggest carvedilol-amiodarone interaction risk; hypothesis-generating from microsomal data and needs clinical confirmation.
It was reported that coadministration of amiodarone with carvedilol increased the serum concentration to dose (C/D) ratio of S-carvedilol in patients with heart failure, but not of R-carvedilol. The aim of the present study was to investigate the effect of amiodarone and its metabolite on the metabolism of R- and S-carvedilol in human liver microsomes (HLM). Oxidation of carvedilol in HLM was evaluated in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH), whereas glucuronidation was evaluated in the presence of uridine 5'-diphosphate (UDP)-glucuronic acid. The oxidation and glucuronidation activities of HLM for S-carvedilol were approximately 2- and 4-fold greater, respectively, than those for R-carvedilol. In the presence of amiodarone (50 microM) and/or desethylamiodarone (25 microM), the oxidation activity for R- and S-carvedilol decreased significantly. In contrast, the glucuronidation activity for R-carvedilol was increased 1.6- and 1.4-fold by amiodarone and desethylamiodarone, respectively, whereas the glucuronidation of S-carvedilol was only slightly changed by amiodarone and desethylamiodarone. These results suggested that inhibition of S-carvedilol oxidation by amiodarone and/or desethylamiodarone is implicated in the increased C/D ratio of S-carvedilol associated with coadministration of amiodarone. On the other hand, the stimulative effect of amiodarone and/or desethylamiodarone on the glucuronidation of R-carvedilol may compensate for the inhibitory effect of those on R-carvedilol oxidation.
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Horiuchi et al. (2010) studied this question. Amiodarone and desethylamiodarone vs. Control (no inhibitor) was evaluated on Oxidation and glucuronidation of R- and S-carvedilol (p=<0.05). Amiodarone and desethylamiodarone significantly decreased the oxidation of R- and S-carvedilol, while increasing the glucuronidation of R-carvedilol by 1.6- and 1.4-fold, respectively.
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