Pharmacokinetics and tissue distribution study of prucalopride in rats by ultra high performance liquid chromatography with tandem mass spectrometry

摘要

A sensitive, reliable and high throughput ultra high performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the determination of prucalopride in rat plasma and various tissues (including heart, liver, spleen, lung, kidney, stomach,small intestine, large intestine, cecum, cerebrum, cerebellum, and ovary). The plasma and tissues samples were treated by protein precipitation with acetonitrile using carbamazepine as an internal standard (IS). Chromatographic separation was performed on a Waters ACQUITY UPLC (R) HSS C18 column (2.1 mm x 50 mm, 1.8 mu m) with a gradient mobile phase consisting of acetonitrile-water (containing 0.1% formic acid) as mobile phase at a flow rate of 0.2 mL/min. The quantification was performed by multiple reactions monitoring mode with m/z 367.99 -> 195.89 for prucalopride and m/z 236.97 -> 194.04 for carbamazepine on a Waters Xevo TQD mass spectrometry equipped with electrospray ionization (ESI) source. The calibration curve was linear in the range of 0.1-100 ng/mL for plasma and various tissues (r >= 0.99) with a lower limit of quantification of 0.1 ng/mL. The recoveries obtained for prucalopride were more than 85%. The validated method was successfully applied to the pharmacokinetics and tissue distribution study of prucalopride after oral administration to rats. The pharmacokinetic parameters were demonstrated as followed: the time to reach peak concentration (T-max) was 1.0 h, and the peak concentration (C-max) was 21.71 +/- 4.28 ng/mL, the half-life (t(1/2)) was 18.21 +/- 0.69 h, and the area under the curve (AUC) was 59.30 +/- 9.43 ngh/mL. Tissue distribution showed the highest level was observed in stomach and intestine, then in liver, which indicated that prucalopride was absorbed firstly in stomach and intestine, and mainly accumulated in liver. It was also the first study to investigate the tissue distribution of prucalopride in rats following oral administration. (C) 2016 Elsevier B.V. All rights reserved.