Stereoselective steady state disposition and action of propafenone in Chinese subjects

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AimsTo investigate the steady state disposition and action of racemic propafenone and its enantiomers and the potential for an enatiomer-enantiomer interaction in Chinese subjects.MethodsEight healthy male Chinese individuals received in a double-blind, randomized, cross-over study racemic propafenone (150 mg every 6 h), (S)-, and (R)-propafenone (150 mg each every 6 h) and placebo orally for 4 days. During the last dosing interval the plasma concentrations of both enantiomers of propafenone were measured and ECG, blood pressure (MAP) and heart rate were monitored.ResultsWhereas the apparent elimination half-life (t1/2,z), mean residence time (MRT) and time to reach peak concentrations (tmax) of (S)- and (R)-propafenone were similar and independent of the administered agent, significant differences were observed in the apparent oral clearance (CLO) of the enantiomers. During dosing with racemic propafenone CLO of (S)- and (R)-propafenone averaged (±s.d.) 1226±751 and 1678±625 ml min−1, respectively (P=0.024). Following the administration of the pure enantiomers CLO of (S)-propafenone increased (P=0.007) to 2028±959 ml min−1 and that of (R)-propafenone was reduced (P=0.042) to 1318±867 ml min−1. Both enantiomers and the racemate caused about a 10% increase in the QRS duration (P<0.05) and PR-interval (P<0.01) when compared with placebo. The increase in maximum exercise heart rate was significantly (P<0.05) attenuated only at 3 h following the administration of the racemate and the S-enantiomer. MAP and QTC were not affected significantly.ConclusionsThese data indicate that the stereoselective disposition of propafenone is similar in Chinese and Caucasian subjects (previously published findings), the (R)-enantiomer being cleared more rapidly. A similar enantiomer-enantiomer interaction also occurred. Thus, when the racemate was given, the elimination of (S)-propafenone was impaired and that of the (R)-form accelerated compared with single enantiomer administration. The results indicate that dosage adjustments are probably not required in Chinese patients receiving propafenone.

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