¹Institute of Clinical Pharmacology, Nanjing Medical University, and the Department of Clinical Pharmacology, Jinling Hospital, Nanjing, Jiangsu, People's Republic of China

Correspondence: Wei M Cai, PhD, Department of Clinical Pharmacology, Jinling Hospital, 305 Zhong-Shan Dong Road, Nanjing 210002, People's Republic of China. E-mail: wmcai@public1.ptt.js.cn

^*Supported in part by National Research Foundation of Overseas Scholar, Beijing, China (grant No. 9701).

Received 5 April 1999; Accepted 17 August 1999.

Abstract

Objective: To determine the effect of 20 mg/day fluoxetine on the pharmacokinetics of propafenone enantiomers and CYP2D6 activity by phenotyping with dextromethorphan.

Methods: Nine healthy Chinese volunteers (seven men and two women) were included in a two-phase study. Dextromethorphan (20 mg) was given before and after subjects took 20 mg/day fluoxetine for 10 days, and the dextromethorphan metabolic ratio was calculated to determine CYP2D6 phenotype. Pharmacokinetic studies of propafenone enantiomers after a single oral 400 mg dose before and after pretreatment with 20 mg/day fluoxetine for 10 days were also conducted in these subjects. Reversed-phase HPLC with precolumn derivatization was used to determine enantiomeric concentrations of propafenone in plasma.

Results: Mean CYP2D6 dextromethorphan metabolic ratios before and after fluoxetine therapy were 0.028 0.031 and 0.080 0.058, respectively (P = .001), indicating that a strong inhibition of CYP2D6 by fluoxetine activity was observed in Chinese subjects. Propafenone metabolism was also impaired significantly after fluoxetine treatment. The elimination half-life, peak concentration, and area under the curve from 0 hours to infinity of two enantiomers after fluoxetine therapy were significantly increased compared with 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). In 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 before 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 inhibition impairs the metabolism of propafenone enantiomers in Chinese subjects. Caution must be exercised when fluoxetine and propafenone are coadministered to avoid potential toxicity.