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

Abstract

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 highperformance 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 0.5mL 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.