Analysis of sex differences in strychnine-intoxicated rats based on metabolic kinetics and metabolomics approaches

Background Drug metabolism varies between men and women owing to differences in body fat distribution and hormone secretion, often necessitating sex-specific dosing. Strychnine, the primary active compound in strychnine-based alkaloids, is used for the treatment of hemiplegia or amblyopia. However, knowledge of sex-based differences in the pharmacokinetics of strychnine remains limited, increasing the risk of dosing errors and potential toxicity in patients. Method Strychnine was administered to healthy and gonadectomized (castrated male and ovariectomized female) rats. Post-administration, orbital blood samples were collected at multiple time points (30, 120, and 720 min) and centrifuged to isolate plasma. The plasma was analyzed for strychnine concentrations and to obtain metabolic kinetic data using high performance liquid chromatography (HPLC)-tandem mass spectrometry and HPLC–time-of-flight mass spectrometry, respectively. The data were used to identify the intrinsic sex-specific metabolic differences between male and female rats. Result Healthy female rats absorbed and metabolized strychnine at a faster rate than healthy male rats, with significantly higher plasma peak concentrations. The metabolic profiles of the rats changed significantly after gonadectomy, suggesting that sex hormones may be involved in the metabolism of strychnine. Significant differences were also observed between the metabolomics of male and female rats, including differences in ABC transporter expression, pyrimidine metabolismand linoleic acid metabolism pathways. Conclusion Significant sex-specific differences exist between the strychnine pharmacokinetics and metabolomics of male and female rats, potentially due to the differential expression of ABC transporter expression, pyrimidine metabolismand linoleic acid metabolism. These findings provide an important reference for sex-specific clinical management of strychnine toxicity.