Effect of fluoxetine on carvedilol pharmacokinetics, CYP2D6 activity, and autonomic balance in heart failure patients

The objective of this study was to examine the pharmacokinetic and pharmaco dynamic consequences of concomitant administration of fluoxetine and carved ilol in heart failure patients. Fluoxetine (20 mg) or matching placebo was administered in a randomized, double-blind, two-period crossover study to 1 0 patients previously identified as extensive metabolizers of CYP2D6 substr ates. Patients were maintained on a carvedilol dose of 25 or 50 mg bid and given fluoxetine/placebo for a minimum of 28 days. Plasma was collected ove r the 12-hour carvedilol dosing interval, and the concentrations of the R() and S(-) enantiomers of carvedilol were measured. CYP2D6 phenotype was as sessed during each study period using dextromethorphan (30 mg). Changes in autonomic modulation between study periods were measured by heart rate vari ability in the time and frequency domains using ambulatory electrocardiogra phic monitoring. Compared to placebo, fluoxetine coadministration resulted in a 77% increase in mean (+/-SD) R(+) enantiomer AUC(0-12) (522 +/- 413 vs . 927 +/- 506 ng.h/mL, p = 0.01) and a nonsignificant increase in S(-) enan tiomer AUC (244 +/- 185 vs. 330 +/- 179 ng.h/ml, p = 0.17). Mean apparent o ral clearance for both enantiomers decreased significantly with fluoxetine administration (R(+): 10.3 +/- 7.2 vs. 4.5 +/- 2.2 mL/min/kg; S(-): 22.5 +/ - 12.3 vs. 12.6 +/- 7.4 mL/min/kg; p 0.004 and 0.03, respectively). No diff erences in adverse effects, blood pressure, or heart rate were noted betwee n treatment groups, and there were no consistent changes in heart rate vari ability parameters. In conclusion, fluoxetine administration resulted in a stereospecific inhibition of carvedilol metabolism, with the R(+) enantiome r increasing to a greater extent than the S(-) enantiomer. However, this in teraction was of little clinical significance in our sample population. Jou rnal of Clinical Pharmacology, 2001;41:97-106 (C) 2001 the American College of Clinical Pharmacology.