Enantioselective assay of nisoldipine in human plasma by chiral high-performance liquid chromatography combined with gas chromatographic-mass spectrometry: applications to pharmacokinetics

Nisoldipine, a second-generation dihydropyridine calcium antagonist, is a r acemate compound used in the treatment of hypertension and coronary heart d isease. This study presents an enantioselective HPLC-GC-MS method for the a nalysis of nisoldipine in human plasma and establishes confidence limits fo r its application to pharmacokinetic studies. Plasma samples were basified and extracted with toluene. The enantiomers were resolved on a Chiralcel (R ) OD-H column using hexane-ethanol (97.5:2.5, v/v) and the (+)- and (-)-fra ctions were collected separately with the diode array detector switched off . For the quantification of the nisoldipine enantiomers a GC-MS with an Ult ra I Hewlett-Packard column was used with the detector operated in the sing le-ion monitoring mode with electron-impact ionization (m/z 371.35 and 270. 20 for nisoldipine and m/z 360.00 for the internal standard, nitrendipine). The method proved to be suitable for pharmacokinetic studies based on the low quantification limit (0.05 ng/ml for each enantiomer) and the broad lin ear range (0.05-50.0 ng/ml for each enantiomer). Low coefficients of variat ion (< 15%) were demonstrated for both within-day and between-day assays. N o interference from drugs associated with nisoldipine treatment was observe d. The enantioselective pilot study on the kinetic disposition of nisoldipi ne administered in the racemic form to a hypertensive patient using a multi ple dose regimen revealed the accumulation of the (+)-enantiomer with an AU C(0-24) (+)/(-) ratio of approximately 8. Both enantiomers were quantified in plasma at a time interval of 24 h. This HPLC-GC-MS method is reliable, s elective and sensitive enough to be used in clinical pharmacokinetic studie s on the enantioselective disposition of nisoldipine in humans. (C) 2001 El sevier Science B.V. All rights reserved.