Stereoselective disposition of nilvadipine, a new dihydropyridine calcium antagonist, in the rat and dog.

The stereoselective disposition of nilvadipine (NV), a new 1,4-dihydropyridine calcium antagonist, was determined in male and female rats, and male dogs. After oral dosing of racemic NV to male rats, the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of the pharmacologically more potent (+)-NV were 0.59-0.60 times those of (-)-NV. The apparent oral clearance (CLo) ratio of (+)- to (-)-NV was 1.69. The plasma elimination of the enantiomers were similar. In female rats, the plasma concentrations and pharmacokinetic parameters of the enantiomers did not significantly differ. In orally-dosed dogs, the Cmax and AUC of (+)-NV were 3.13 and 3.83 respectively times greater than those of (-)-NV. The enantiomeric ratio of CLo was 0.27, and the half-lives of the enantiomers were similar. After intravenous dosing to dogs, the plasma concentrations of (+)- and (-)-NV declined biexponentially with similar t1/2 beta values. The AUC of (+)-NV was 1.56 times more than that of (-)-NV. The enantiomeric ratios of systemic clearance and volume of distribution at steady state were 0.64 and 0.81, respectively. Thus, the stereoselective disposition of NV was species-dependent and sex-related in rats, and was dosing route-dependent in dogs. The free fraction value for protein binding of (+)-NV in dog plasma was only 0.50-0.51 times that of (-)-NV. The enantiomeric ratios of those values in male and female rat plasma were 1.14 and 0.98, respectively.