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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 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 approximately 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 microg 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 t1/2, and Cmax 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 approximately 3 fold differences in Cmax, CL and AUC compared with EMs. The correlation coefficients (rs ) between dextromethorphan metabolic ratio (lg MR) and pharmacokinetic parameters (Cmax, 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.