Simultaneous modeling of pharmacokinetics and pharmacodynamics of propafenone in healthy subjects

Aim: To study the simultaneous modeling of pharmacokinetics and pharmacodyn amics (PK-PD) of propafenone (Pro) in healthy subjects. Methods: Ten healthy Chinese volunteers, 5 extensive metabolizers ( EM) and 5 intermediate metabolizers (IM) of CYP2D6, received a single dose (400 mg ) of Pro hydrochloride. The blood samples and electrocardiogram (ECG) measu rements were taken after administration over 15h period. The concentrations of Pro in plasma were measured by a reverse-phase HPLC. PR interval was us ed as an average value of 10 PR interval measurements. Results: There was a delay between Pro level and percentage of PR interval prolongation. After PK-PD simulating, the relationship between effect conce ntration (Ce) and the effect met the sigmoid E-max model. CYP2D6 (EM & IM) played an important role in both pharmacokinetics and pharmacodynamics whic h produced by Pro. The AUC (mug.h.L-1) of IM group was significantly higher than that of EM group (5126 +/- 1030 vs 2948 +/- 1230, P<0.05). Whereas Ce -50 (<mu>g/L) was also greater in IM group than in EM group (747 +/- 281 vs 359 +/- 123, P<0.05). On the other hand, <gamma> of EM group was about one fold larger than that of IM group (P<0.05). Conclusion: CYP2D6 phenotype of human may influence not only pharmacokineti c of Pro but also its pharmacological effects.