Stereoselective pharmacokinetics and pharmacodynamics of disopyramide and its metabolite in rabbits

Abstract

The extent to which interactions between enantiomers of disopyramide and between disopyramide and its metabolite, mono-N-dealkylated disopyramide (MND), contribute to stereoselectivity of the anti-arrhythmic effect has been investigated in rabbits by measuring the prolongation of the QUc interval. The plasma unbound fraction of disopyramide enantiomers was constant at a concentration range of 1.44-28.9 microM. An intravenous infusion study of the disopyramide enantiomer or racemate suggested that the S-enantiomer had a pharmacological effect, determined by linear regression analysis, approximately 3.3-times more potent than that of the R-enantiomer. Furthermore, the effect caused by racemic disopyramide was the sum of that elicited by both enantiomers individually. No significant difference was observed between the slope of linear regression analysis of intravenous infusion and that of intravenous bolus injection. Single intravenous bolus injection of MND did not affect the QUc intervals. In conclusion, the S-enantiomer of disopyramide was approximately 3.3-times more potent pharmacologically than the R-enantiomer. The relationship between plasma concentration of the disopyramide enantiomers and pharmacological effect was the sum of each enantiomer individually.