SIMULTANEOUS ASSESSMENT OF THE INTRAVENOUS AND ORAL DISPOSITION OF THE ENANTIOMERS OF RACEMIC NIMODIPINE BY CHIRAL STATIONARY-PHASE HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY AND GAS-CHROMATOGRAPHY MASS-SPECTROSCOPY COMBINED WITH A STABLE ISOTOPE TECHNIQUE

An enantioselective method of high specificity and sensitivity for the determination of the enantiomers of two racemic 1,4-dihydropyridine compounds after simultaneous oral (po) and intravenous (iv) administration is reported. The method is suitable for the simultaneous administration by two different routes of a racemic drug labeled with stable isotopes and unlabeled racemate. For workup, an internal racemic standard labeled with a different number of stable isotopes is added. After separation of the enantiomers by chiral stationary-phase high-performance liquid chromatography and subsequent analysis by gas chromatography/mass spectroscopy (GC/MS) with selected ion detection, the R and S enantiomer concentrations arising from iv and po administration can be precisely measured because of their mass difference. This method has been applied to assess the disposition of the R and S enantiomers of nimodipine and nitrendipine after simultaneous iv and po administration. The assay is highly specific and sensitive, with a limit of quantification per enantiomer of 0.1 ng/mL after extraction of 0.5 mL of human serum samples and monitoring the M-. ions in the electron capture, negative ion chemical ionization mode. The calibration curve was linear in the range 0.1-100 ng/mL. Within- and between-day precision were satisfactory (coefficient of variation, < 10%). Enantiomeric excess in the range 0-100% could be accurately determined. Comparison of the enantioselective method with the achiral method (GC/MS only) gave good agreement.