Aims To determine role of CYP2D6 activity in the pharmacokinetics of propafenone (PPF) enantiomers in native Chinese subjects. Methods Sixteen extensive metabolizers (EMs) and one poor metabolizer (PM), whose phenotype had been previously assessed with dextromethorphan metabolic phenotyping, were enrolled. Blood samples (0~15 h) were taken after oral administration of a single dose (400 mg ) of racemic-propafenone hydrochloride. A reverse-phase h.p.l.c. method with pre-column derivatization was employed to quantitate enantiomeric concentrations of propafenone in plasma. Results For the EM subjects, S-PPF was less rapidly metabolized and had higher peak plasma concentrations than R-PPF (413±143 vs 291±109 ng ml −1 , P<0.001).The AUC was markedly higher for S-PPF than for R-PPF (2214±776 vs 1639±630 mg h l −1 , P<0.001), whereas the clearance of S-PPF was significantly lower than that of R-PPF (96.0±39.0 vs 138±78 l h −1 , P<0.01). There were no differences in t 1/2 , and C max between the two isomers ( P >0.05). In the one PM subject, not only did S-PPF appear to undergo less rapid metabolism than R-PPF, but the subject also showed 2~3 fold differences in C max , CL and AUC compared with EMs. The correlation coefficients (r s ) between dextromethorphan metabolic ratio (lg MR) and pharmacokinetic parameters (C max , CL and AUC) were 0.63, −0.87, 0.87 for S-PPF and 0.57, −0.73, 0.86 for R-PPF, respectively. Conclusions Our results suggest that CYP2D6 activity contributes to the pharmacokinetic variability of propafenone enantiomers in Chinese subjects.Keywords: propafenone, enantiomer, pharmacokinetics, CYP2D6, phenotype, Chinese metabolic phenotyping in a Chinese population has Introduction shown that Chinese extensive metabolizers (EMs) consisted of about 99% (119/120) of the Chinese population Propafenone (PPF), a commonly used antiarrhythmic agent, is given clinically as a racemic mixture of S-PPF and that only one subject could be classified as a PM with respect to CYP2D6 [4]. The purpose of this study and R-PPF [1]. The two enantiomers are metabolized at different rates in Caucasians, with the R-PPF being was to examine the dispositon of propafenone enantiomers in 16 EMs and one PM to determine if stereoselective eliminated faster than the S-PPF [2]. Propafenone is biotransformed mainly through cytochrome P450 2D6 pharmacokinetics of propafenone occurs and whether the kinetics of propafenone enantiomers depends on CYP2D6 (CYP2D6) to the active metabolite 5-hydroxypropafenone (5-OH PPF) and less importantly through activity in Chinese subjects. CYP3A4 to N-desalkylpropafenone ( N-desalkyl PPF). Previous work has shown that the metabolism of PPF is Methods polymorphic and genetically determined, resulting in higher plasma drug concentrations in the 7% of Caucasians Subjects who are poor metabolizers (PMs) with respect to Seventeen (eleven men and six women) healthy native CYP2D6 [3]. Our recent research on dextromethorphan Chinese subjects (age range, 23 to 45 years; weight range, 50 to 75 kg) were recruited fr...