Abstract
The separation of enantiomers of dihydropyridine derivatives by high-performance liquid chromatography (HPLC) was studied using modified Pirkle-type chiral stationary phases. Enatioseparations of manidipine and nicardipine were achieved by a normal-phase mobile phase utilizing n-hexane-l, 2-dichloroethane-methanol-trifluoroacetic acid on the urea-derivative type chiral statinary phase (SUMICHIRAL OA-4500). The enantioselective HPLC methods of manidipine and nicardipine in human plasma involve a rapid and simple extraction based on a bonded-phase extraction, which were applied to an enatioselective pharmacokinetic study in healthy subjects. Also, the effects of grapefruit juice on the stereoselective dispositions of manidipine and nicardipine in healthy subjects were examined. (+)-Manidipine plasma level was 1.5 fold higher than (-)-manidipine, and both enantiomers plasma level increased to 2.3 fold with grapefruit juice. Additionally, on the study of nicardipine, subjects were received intravenous doses and oral doses. After oral administration, grapefruit juice significantly increased the plasma concentrations of (+)-nicardipine and (-)-nicardipine, but not affect after intravenous administration. It is suggested that grapefruit juice inhibited CYP3A4-mediated presystemic metabolism in the small intestine.
