Fluoxetine impairs the CYP2D6-mediated metabolism of propafenone enantiomers in healthy Chinese volunteers

Objective: To determine the effect of 20 mg/day fluoxetine on the pharmacok inetics of propafenone enantiomers and CYP2D6 activity by phenotyping with dextromethorphan. Methods: Nine healthy Chinese volunteers (seven men and two women) were inc luded in a two-phase study. Dextromethorphan (20 mg) was given before and a fter subjects took 20 mg/day fluoxetine for 10 days, and the dextromethorph an metabolic ratio was calculated to determine CYP2D6 phenotype, Pharmacoki netic studies of propafenone enantiomers after a single oral 400 mg dose be fore and after pretreatment with 20 mg/day fluoxetine for 10 days were also conducted in these subjects. Reversed-phase HPLC with precolumn derivatiza tion was used to determine enantiomeric concentrations of propafenone in pl asma. Results: Mean CYP2D6 dextromethorphan metabolic ratios before and after flu oxetine therapy were 0.028 +/- 0.031 and 0.080 +/- 0.058, respectively (P = .001), indicating that a strong inhibition of CYP2D6 by fluoxetine activit y was observed in Chinese subjects. Propafenone metabolism was also impaire d significantly after fluoxetine treatment. The elimination half-life, peak concentration, and area under the curve from 0 hours to infinity of two en antiomers after fluoxetine therapy were significantly increased compared wi th those at baseline (P < .01), whereas oral clearance decreased from 75.01 +/- 17.69 L/h to 49.36 +/- 8.62 L/h for S-propafenone (P = .005) and from 107.62 +/- 33.82 L/h to 70.60 +/- 12.42 L/h for R-propafenone (P = .027). I n addition, fluoxetine increased the peak concentration of S-propafenone by 39% and that of R-propafenone by 71% (P < .05). A significant increase of the time to reach peak concentration was observed only in the R-enantiomer and not in the S-enantiomer of propafenone after fluoxetine therapy, There were no differences in the percentage changes of PR and QRS intervals befor e or after fluoxetine pretreatment at the time observed (P > .05). Conclusion: We conclude that fluoxetine may cause significant inhibition of the CYP2D6 activity as determined by dextromethorphan phenotyping, This in hibition impairs the metabolism of propafenone enantiomers in Chinese subje cts. Caution must be exercised when fluoxetine and propafenone are coadmini stered to avoid potential toxicity.