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.
Highlights
Ketamine (KET), originally used as a surgical anesthetic, became a popular street drug in the USA in the 1970s
Typical UPLC-MS/MS chromatograms of blank plasma and plasma samples collected from the orbital vein of rats are shown in Figure 3, demonstrating that there were no major interference from endogenous substances in the analysis of the compounds, and good selectivity was achieved
Y1 represents the ratio of the peak intensity of KET to the internal standard, and X1 represents the concentration of KET in plasma; Y2 represents the ratio of the peak intensity of NK to the internal standard, and X2 represents the concentration of NK in plasma
Summary
Ketamine (KET), originally used as a surgical anesthetic, became a popular street drug in the USA in the 1970s. Based on its dissociative anesthetic properties, KET generates visual and auditory distortions and a sense of floating and dissociation in abusers [2]. L-THP has analgesic, sedative, and anxiolytic properties. Pharmacological studies demonstrated that L-THP is an antagonist of dopamine (DA) D1 and D2 receptors [5]. The DA system has been reported to play an important role in drug addiction. As a nonselective DA antagonist, L-THP has recently emerged as a promising agent for treating addiction to many types of drugs, including cocaine [6, 7], BioMed Research International methamphetamine [8], and oxycodone [9]. L-THP showed a potential therapeutic effect on KET addiction [10]. The pharmacokinetic effects of L-THP on KET remain unclear
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