Analysis of sex difference in strychnine-intoxicated rat based on the combination of metabolic kinetics and metabolomics
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Background
Drug metabolism va-specific dosing. Strychnine, the primary active compound in strychnine-based alkaloids, is used for treatment of hemiplegia or amblyopia. However, knowledge of sex-based difference in the pharmacokinetics of strychnine remains limited, increasing the risk of dosage error and potential toxicity in patient.ries between men and women derived from the difference in body fat distribution and hormone secretion, necessitating sex.
Method
Rats were divided into intact (possessing reproductive organ) and gonadectomized (GDX) groups, including 6 males and 6 females in each one. In the GDX rat group, testes were removed from male rat at 5 weeks of age, while ovaries were removed from female rat. The GDX rats were maintained for an additional 15 days. All intact and GDX rats were tested at 8 weeks of age. Both intact and GDX rats were subjected to acute strychnine exposure through an oral dose of 0.59 mg/kg aqueous strychnine nitrate solution. Blood sampleswere collected from orbital vein into a centrifuge tube containing sodium heparin at following time points: 5, 10, 15, 30, and 45 min, as well as 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h. In the metabolomics experiments, male and female rats were divided into experimental and control groups. Each group containing 10 males and 10 females. The experimental group was orally administered 0.59 mg/kg of aqueous strychnine nitrate, while the control group was given the same dose of ultrapure water. Blood samples were collected from the orbital vein at 30 min, 2 h, and 12 h following administration. The plasma concentration of strychnine was quantified using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), while the metabolic kinetics data was acquired via HPLC-time-of-flight mass spectrometry (HPLC-TOF-MS). These data was subsequently analyzed to elucidate the intrinsic sex-specific metabolic difference between male and female rats.
Result
Intact female rats metabolized strychnine more slowly than male rats, with significantly higher peak plasma concentrations. Moreover, the peak concentrations in both male and female rats decreased after gonadectomy, the plasma peak concentration in GDX female rats remained significantly higher than that in GDX male rats.The metabolic profile of the rat 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, such as ABC transporter expression, pyrimidine metabolism, and linoleic acid metabolism pathways.
Conclusion
Significant sex-specific difference exists between strychnine pharmacokinetics and metabolomics of male and female rats, potentially due to the differential expression of ABC transporter expression, pyrimidine metabolism and linoleic acid metabolism. These findings provide an important reference for sex-specific clinical management of strychnine toxicity.
Plain Language summary
Strychnine is a medication used for the treatment of muscle weakness and visual issues. However, it affects males and females differently. If dosing is not customized according to sex, it may lead to toxicity. Therefore, we explored the mechanisms underlying the toxic effects of strychnine in male and female rats (both intact and gonadectomized). We found that female rats showed higher blood drug levels. Moreover, the peak blood drug concentrations of both male and female rats decreased after gonadectomy. Additionally, sex-specific differences were observed in the expression of ABC transporter expression, pyrimidine metabolism and linoleic acid metabolism. These differences may explain why strychnine affects male and female rats differently.
