Pharmacokinetics and pharmacodynamics of pirmenol enantiomers in coronary artery ligated dogs

Abstract

The pharmacokinetics and pharmacodynamics of pirmenol enantiomers were investigated in coronary artery ligated mongrel dogs. Reduction in frequency of premature ventricular complexes (PVCs) was determined following intravenous administration of 5-mg/kg doses of racemic pirmenol ( n = 5), (+)-pirmenol ( n = 4), and (−)-pirmenol ( n = 4), each given as a 5-min infusion. Electrocardiographic signals and blood samples were obtained serially over a 4-h period. Pirmenol enantiomer concentrations in plasma were determined by a stereospecific assay. Following the racemate dose, (−)-pirmenol had 47% lower clearance and 33% lower steady-state distribution volume than (+)-pirmenol. These differences could be mostly explained by stereoselective plasma protein binding, reflected in a 58% higher unbound fraction for (+)-pirmenol compared with (−)-pirmenol following racemate administration. Unbound pirmenol distribution volumes were nearly identical for both enantiomers, and unbound clearance was only 16% lower for (−)-pirmenol than (+)-pirmenol following administration of the racemate. Similar trends were observed for pirmenol enantiomers administered individually. Both pirmenol enantiomers were equally effective in arrhythmia suppression. The antiarrhythmic response of coronary artery ligated dogs to pirmenol was described by a sigmoid E max model, and no statistically significant differences were observed in the pharmacodynamic parameters [i.e., EC 50 (plasma concentration at 50% of maximum drug effect), S (constant that reflects the sigmoidal shape of the effect–concentration curve), and EC 90 (plasma concentration at 90% of maximum drug effect)] for (+)-pirmenol, (−)-pirmenol, or pirmenol racemate.