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 i.v. and p.o. 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 i.v. and p.o. 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.
Fischer
C
C
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
Schönberger
F
F
Mück
W
W
Heuck
K
K
Eichelbaum
M
M
D000284:Administration, Oral; D000328:Adult; D002247:Carbon Isotopes; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D006801:Humans; D007275:Injections, Intravenous; D007553:Isotope Labeling; D008297:Male; D009553:Nimodipine / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D009568:Nitrendipine / Q000097:blood / Q000493:pharmacokinetics; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D014018:Tissue Distribution
D002247:Carbon Isotopes; D009553:Nimodipine; D009568:Nitrendipine