Role of pharmacokinetics and metabolism in drug discovery and development.
The metabolism and pharmacokinetics of (S)-(+)- and (R)-(-)-disopyramide (DP) were compared in laboratory animals. In rats, after oral administration of (S)-(+)-DP phosphate salt at a dose of 38.8 mg of DP free base per kg, the mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 1.43 micrograms/ml and 4.47 micrograms . hr/ml, respectively, and after (R)-(-)-DP administration, the values were 4.93 micrograms/ml and 17.05 micrograms . hr/ml, respectively. Similar recoveries (approximately 55% of the dose) of DP and its metabolites in the urine and bile of rats were obtained after administration of the individual (S)-(+)- and (R)-(-)-enantiomers of DP. These results indicate similar oral absorption of the two enantiomers, but greater metabolism with (S)-(+)-DP in rats. In dogs, the AUC of DP after iv administration of (R)-(-)-DP phosphate salt at a dose of 15 mg of DP free base per kg was 1.6 times greater than that after (S)-(+)-DP phosphate salt. Inasmuch as volumes of distribution of the two enantiomers were similar, this difference can be attributed to a difference in the elimination rates of the enantiomers. After an oral dose, the difference in AUC of the two enantiomers was greater than that after an iv dose. The mean values of Cmax and AUC after a 15-mg/kg oral dose of (S)-(+)-DP were 1.32 micrograms/ml and 4.07 micrograms . hr/ml, respectively, and with (R)-(-)-DP the values were 2.88 micrograms/ml and 9.21 micrograms . hr/ml, respectively. The Cmax and AUC of the total drug-related materials (drug plus its metabolites) were similar. These results, together with the similarity in the urinary excretion of total drug related compounds, indicated that after equivalent doses of the two enantiomers, oral absorptions were similar, but the first-pass metabolism was greater with (S)-(+)-DP. The present study also demonstrated that N-dealkylation in dogs and arylhydroxylation in rats are stereoselective metabolic pathways, thus illustrating species differences in the stereoselective metabolism of DP.