PHARMACOKINETICS AND PHARMACODYNAMICS OF PIRMENOL ENANTIOMERS IN CORONARY-ARTERY LIGATED DOGS

The pharmacokinetics and pharmacodynamics of pirmenol enantiomers were investigated in coronary artery ligated mongrel dogs. Reduction in fr equency of premature ventricular complexes (PVCs) was determined follo wing 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 concentration s in plasma were determined by a stereospecific assay. Following the r acemate dose, (-)-pirmenol had 47% lower clearance and 33% lower stead y-state distribution volume than (+)-pirmenol. These differences could be mostly explained by stereoselective plasma protein binding, reflec ted in a 58% higher unbound fraction for (+)-pirmenol compared with (- )-pirmenol following racemate administration. Unbound pirmenol distrib ution volumes were nearly identical for both enantiomers, and unbound clearance was only 16% lower for (-)-pirmenol than (+)-pirmenol follow ing administration of the racemate. Similar trends were observed for p irmenol enantiomers administered individually. Both pirmenol enantiome rs were equally effective in arrhythmia suppression. The antiarrhythmi c response of coronary artery ligated dogs to pirmenol was described b y 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 reflec ts 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.