Stereoselective quantitative analysis of ranolazine in plasma and tissue samples: application in pharmacokinetics and tissue distribution studies

Abstract

This study aimed to develop a rapid and sensitive reversed-phase mode high-performance liquid chromatography-electrospray ionization coupled with a tandem mass spectrometry method for the simultaneous determination of ranolazine enantiomers in rat plasma and tissues. The obtained biological samples were pretreated with the liquid–liquid extraction method, and methyl tert-butyl ether was employed as the extracting agent. The efficient stereo separation of target compounds was achieved on a Chiralcel OD-RH column by using the mobile phase consisting of acetonitrile–2 mM aqueous ammonium acetate (80 : 20, v/v) at a flow rate of 0.6 mL min⁻¹. The analytes were detected by multiple reaction monitoring in positive ion mode with the mass transitions at m/z 428.20 > 279.50 (ranolazine) and 219.80 > 128.06 (ornidazole, internal standard). Furthermore, the elution peak order on the Chiralcel OD-RH column was confirmed by the recorded and calculated electronic circular dichroism spectrum. The results of this pharmacokinetic study revealed that the C_max and AUC_0−t values of R-(+)-ranolazine were 2.05 and 2.72 times higher than those of S-(−)-ranolazine. Compared with S-(−)-ranolazine, R-(+)-ranolazine displayed stronger absorption capability in rat plasma and a slower metabolism rate in major organs of rats. The highest content of R-(+)-ranolazine was in the liver, followed by the kidneys, heart, lungs and spleen. It is noteworthy that this is the first stereoselective report regarding the pharmacokinetics and tissue distribution of ranolazine in vivo, which may benefit instructing the clinical application for safer treatment.