Pharmacokinetic Effects of l -Tetrahydropalmatine on Ketamine in Rat Plasma by Ultraperformance Liquid Chromatography Tandem Mass Spectrometry

Abstract

Male Sprague-Dawley rats (n=18) were randomly divided into three groups: a saline group (20 mL/kg by gavage), a ketamine (KET) group (100 mg/kg by gavage), and a KET (the same routes and doses) combined with levo-tetrahydropalmatine (l-THP; 40 mg/kg by gavage) group (n=6). Blood samples were acquired at different time points after drug administration. A simple and sensitive ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was established to determine the concentrations of KET and its metabolite, norketamine (NK), in rat plasma. Chromatographic separation was achieved using a BEH C18 column (2.1 mm×50 mm, 1.7 μm) with chlorpheniramine maleate (Chlor-Trimeton) as an internal standard (IS). The initial mobile phase consisted of acetonitrile-water with 0.1% methanoic acid (80: 20, v/v). The multiple reaction monitoring (MRM) modes of m/z 238.1→m/z 179.1 for KET, m/z 224.1→m/z 207.1 for NK, and m/z 275→m/z 230 for Chlor-Trimeton (IS) were utilized to conduct a quantitative analysis. Calibration curves of KET and NK in rat plasma demonstrated good linearity in the range of 2.5-500 ng/mL (r>0.9994), and the lower limit of quantification (LLOQ) was 2.5 ng/mL for both. Moreover, the intra- and interday precision relative standard deviation (RSD) of KET and NK were less than 4.31% and 6.53%, respectively. The accuracies (relative error) of KET and NK were below -1.41% and -6.07%, respectively. The extraction recoveries of KET and NK were more than 81.23±3.45% and 80.42±4.57%, respectively. This sensitive, rapid, and selective UPLC-MS/MS method was successfully applied to study the pharmacokinetic effects of l-THP on KET after gastric gavage. The results demonstrated that l-THP could increase the bioavailability of KET and promote the metabolism of KET. The results showed that l-THP has pharmacokinetics effects on KET in rat plasma.