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 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.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34490/1/7_ftp.pd

Stereoselective high-performance liquid chromatographic assay for pirmenol enantiomers in dog plasma

Pirmenol enantiomers in dog plasma were quantified using a stereospecific high-performance liquid chromatographic method with ultraviolet detection at 262 nm. Racemic pirmenol and internal standard, (+)-propranolol, were isolated from dog plasma by a three-step extraction procedure using toluene, 0.1 M hydrochloric acid and hexane, respectively. A chiral analytical column (Chiralcel OJ) was used with a mobile phase consisting of hexane--isopropanol--diethylamine (98.9:1.0:0.1). Linear calibration curves were obtained in the concentration range 0.0200-5.00 [mu]g/ml for each enantiomer. Precision of the method, expressed as coefficient of variation for nine quality control samples, was 7.1% for (+)-pirmenol and 6.4% for (-)-pirmenol. Bias was +/-2.2% for (+)-pirmenol and +/-1.5% for (-)-pirmenol in quality control samples.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28977/1/0000004.pd

Pharmacokinetic and pharmacodynamic evaluation of pirmenol enantiomers.

Pirmenol is a chiral compound being developed in the racemic form as an antiarrhythmic agent. Pharmacokinetics and pharmacodynamics of pirmenol were studied in a dog model of ventricular arrhythmia and in patients with premature ventricular contractions (PVCs) to determine if any advantage exists for the use of either enantiomer over the racemate. Reduction in frequency of PVCs was determined following intravenous administration of 5 mg/kg pirmenol racemate (n = 5), (+)-pirmenol (n = 4), or ($-$)-pirmenol (n = 4) to mongrel dogs with induced ventricular arrhythmia by coronary artery ligation. Electrocardiographic signals and blood samples were obtained serially over 4 hours. Pharmacokinetics of pirmenol enantiomers and pharmacodynamics of pirmenol racemate were also investigated in twelve patients with PVCs following repeated oral administration of racemic pirmenol at 100 mg and 200 mg every 12 hours. Ambulatory electrocardiographic (Holter) monitoring was performed and serial blood samples were collected after the seventh dose at each dose level. In both studies (dog and human), pirmenol enantiomer concentrations in plasma were determined using a stereospecific liquid chromatographic assay and protein binding was assessed using equilibrium dialysis. Pharmacokinetic differences between unbound pirmenol enantiomers are minimal in the dog. Higher concentrations of total ($-$)-pirmenol in plasma are mostly a result of more extensive protein binding in dogs as compared to (+)-pirmenol. In patients, ($-$)-pirmenol is also more highly bound in plasma than is (+)-pirmenol. However, similar plasma enantiomer concentrations are observed for total pirmenol in patients since the more rapidly cleared unbound ($-$)-pirmenol is also more extensively bound to plasma proteins. Based on the dog model of induced ventricular arrhythmia, pirmenol enantiomers are equally effective in PVC suppression. Therefore, equivalent unbound plasma concentrations of separate enantiomers or racemate should result in an equivalent antiarrhythmic effect. Percent reduction in PVCs can be correlated with plasma pirmenol concentrations in a sigmoid-type relationship in both dogs and humans. Both species show a large variability in antiarrhythmic response to pirmenol. Higher concentrations were required for PVC suppression in the acute model of arrhythmia in the dog than for patients with PVCs; on average, pharmacodynamic parameters for pirmenol racemate differed by less than 5-fold between species. Based on pharmacokinetic data alone, there does not appear to be an advantage for development of either enantiomer over the pirmenol racemate. Although pharmacodynamic data of pirmenol enantiomers are similar in dogs, it is uncertain whether or not pirmenol enantiomers will have similar dynamic activities in humans, since in the absence of regulatory approval to administer individual enantiomers, only racemate has been studied to date.Ph.D.PharmaceuticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/104484/1/9527654.pdfDescription of 9527654.pdf : Restricted to UM users only