Stereoselective steady state disposition and action of propafenone in Chinese subjects

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Abstract

Aims

To investigate the steady state disposition and action of racemic propafenone and its enantiomers and the potential for an enatiomer-enantiomer interaction in Chinese subjects.

Methods

Eight 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.

Results

Whereas 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.

Conclusions

These 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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