The influence of CYP2D6 activity on the kinetics of propafenone enantiomers in Chinese subjects

Aims To determine role of CYP2D6 activity in the pharmacokinetics of propaf enone (PPF) enantiomers in native Chinese subjects. Methods Sixteen extensive metabolizers (EMs) and one poor metabolizer (PM), whose phenotype had been previously assessed with dextromethorphan metabol ic phenotyping, were enrolled. Blood samples (0 similar to 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 derivatizat ion was employed to quantitate enantiomeric concentrations of propafenone i n plasma. Results For the EM subjects, S-PPF was less rapidly metabolized and had hig her 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 mu g 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 t he two isomers (P>0.05). In the one PM subject, not only did S-PPF appear t o undergo less rapid metabolism than R-PPF, but the subject also showed 2 s imilar to 3 fold differences in C-max, CL and AUC compared with EMs. The co rrelation 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 pha rmacokinetic variability of propafenone enantiomers in Chinese subjects.