Advanced UPLC-MS/MS Method for the Quantification of SIPI6398 in Rat Plasma and Its Pharmacokinetic Characterization

SIPI6398 is a novel anti-schizophrenia agent with a new mechanism of action and demonstrates better target selectivity and safety compared to its competitors. However, few in vivo studies on the pharmacokinetics and bioavailability of SIPI6398 have been performed. A rapid and simple ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) approach was developed for accurate quantification of SIPI6398 in rat plasma. A simple protein precipitation of acetonitrile-methanol (9 : 1, v/v) was used to treat plasma. Chromatography was performed on a UPLC HSS T3 column (50 mm × 2.1 mm, 1.8 μm) at a flow rate of 0.4 ml/min. The mobile phase consisted of acetonitrile-water (with 0.1% formic acid) and gradient elution was used, and the elution time was 4 minutes. Quantitative analysis was performed using electrospray ionization (ESI) in positive ion detection mode with multiple reaction monitoring (MRM) mode. To evaluate the pharmacokinetics and bioavailability, SIPI6398 was administered to rats in two different ways: oral (4 mg/kg) and intravenous (2 mg/kg) administration. The calibration curve for the UPLC-MS/MS approach shows excellent linearity in the range of 1–2000 ng/mL with an r value above 0.99. The precision, accuracy, recovery, matrix effect, and stability results all meet the criteria established for biological analytical methods. The UPLC-MS/MS method was successfully applied it to pharmacokinetics study of SIPI6398. The bioavailability of SIPI6398 was calculated to be 13.2%. These studies have the potential to contribute towards a more comprehensive comprehension of the pharmacokinetics and bioavailability of SIPI6398.