PHARMACOKINETICS OF PIRMENOL ENANTIOMERS AND PHARMACODYNAMICS OF PIRMENOL RACEMATE IN PATIENTS WITH PREMATURE VENTRICULAR CONTRACTIONS

The pharmacokinetics and pharmacodynamics of pirmenol were investigate d in 12 patients with premature ventricular contractions (PVCs) after oral administration of racemic pirmenol, 100 mg and 200 mg every 12 ho urs. Holter monitoring was performed and serial blood samples were col lected after the seventh doses. Plasma concentrations of pirmenol enan tiomer were determined using a stereospecific liquid chromatographic a ssay. Clearance of total (-)-pirmenol was 20% higher than that of tota l (+)-pirmenol, and the difference in unbound clearance was 45% betwee n enantiomers. Total pirmenol showed a smaller difference because of s tereoselective protein binding, with 25% (100-mg dose) or 27% (200-mg dose) higher fraction unbound for (+)-pirmenol than for (-)-pirmenol. Distribution volume was similar for both enantiomers. Dose-dependent c learance was observed for unbound pirmenol enantiomers, as both enanti omers showed 20% lower unbound clearance at the higher dose. Antiarrhy thmic effect (% reduction in PVCs from baseline) was correlated with p lasma concentrations of pirmenol using a sigmoid maximum drug effect m odel, and patients showed a large variability in their antiarrhythmic response to plasma concentrations of pirmenol. The median value for mi nimum effective plasma concentration of racemic pirmenol was 1.5 mu g/ mL.