Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition · 2025
[Effect of High-Altitude Hypoxia on the Pharmacokinetics and Brain Distribution of Phenytoin Sodium in Epileptic Rats].
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Zhang Xiaojing, Zhong Yan, Mu Hongfang, Li Wenbin, Yang Xiaomin, Wang Rong
Аннотация
OBJECTIVE: To investigate the effects of high-altitude hypoxic environment on the pharmacokinetic characteristics and brain tissue distribution of phenytoin sodium in epileptic rats.
METHODS: A total of 70 male SPF-grade Wistar rats aged 2 months and weighing (200 ± 20) g were used in the study. An epilepsy model was induced in the rats using the lithium chloride-pilocarpine method. The successfully modeled rats were randomly assigned to a normoxic treatment group and a high-altitude hypoxic treatment group. Phenytoin sodium was administered via intragastric gavage at a dose of 50 mg/kg in both groups. Blood samples were collected from the orbital venous plexus before treatment and 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 h post treatment. The animals were euthanized after the final blood collection, and samples of the liver and the whole brain tissue were collected. In the brain tissue distribution experiment, brain tissue samples were collected at 0.5, 1, 2, and 4 h after drug administration. The concentration of phenytoin sodium in rat plasma and brain tissue was determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the pharmacokinetic parameters were calculated using WinNolin 8.1 software. The expression levels of CYP2C9 in liver tissue and those of P-gp in brain tissue of epileptic rats were determined by Western blot.
RESULTS: Compared with those in the normoxia group, the peak concentration, peak time, and half-life of phenytoin sodium in the high-altitude hypoxia group were significantly decreased by 46.0%, 42.3%, and 55.5%, respectively (all P < 0.05); the clearance rate was significantly increased by 162.0% (P < 0.05); and the area under the curve of plasma concentration-time curve was decreased by 45.6% (P < 0.01). At 0.5, 1, and 2 hours after administration, compared with that in the normoxia treatment group, the concentration of phenytoin sodium in the brain tissue of the high-altitude hypoxia treatment group was significantly decreased by 78.1%, 63.5%, and 32.5%, respectively (all P < 0.05). Western blot results showed that the expression levels of CYP2C9 in the liver tissue and P-gp in the brain tissue of rats in the high-altitude hypoxia group were approximately 1.78 and 1.65 times higher than those in the normoxia group, respectively (both P < 0.05).
CONCLUSION: The hypoxic environment at high altitudes can promote the metabolism of phenytoin sodium, reduce its absorption efficiency, and change the characteristics its distribution in the brain, which may be related to the up-regulation of the expression of CYP2C9 in the liver and that of P-gp in the brain.
METHODS: A total of 70 male SPF-grade Wistar rats aged 2 months and weighing (200 ± 20) g were used in the study. An epilepsy model was induced in the rats using the lithium chloride-pilocarpine method. The successfully modeled rats were randomly assigned to a normoxic treatment group and a high-altitude hypoxic treatment group. Phenytoin sodium was administered via intragastric gavage at a dose of 50 mg/kg in both groups. Blood samples were collected from the orbital venous plexus before treatment and 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 h post treatment. The animals were euthanized after the final blood collection, and samples of the liver and the whole brain tissue were collected. In the brain tissue distribution experiment, brain tissue samples were collected at 0.5, 1, 2, and 4 h after drug administration. The concentration of phenytoin sodium in rat plasma and brain tissue was determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the pharmacokinetic parameters were calculated using WinNolin 8.1 software. The expression levels of CYP2C9 in liver tissue and those of P-gp in brain tissue of epileptic rats were determined by Western blot.
RESULTS: Compared with those in the normoxia group, the peak concentration, peak time, and half-life of phenytoin sodium in the high-altitude hypoxia group were significantly decreased by 46.0%, 42.3%, and 55.5%, respectively (all P < 0.05); the clearance rate was significantly increased by 162.0% (P < 0.05); and the area under the curve of plasma concentration-time curve was decreased by 45.6% (P < 0.01). At 0.5, 1, and 2 hours after administration, compared with that in the normoxia treatment group, the concentration of phenytoin sodium in the brain tissue of the high-altitude hypoxia treatment group was significantly decreased by 78.1%, 63.5%, and 32.5%, respectively (all P < 0.05). Western blot results showed that the expression levels of CYP2C9 in the liver tissue and P-gp in the brain tissue of rats in the high-altitude hypoxia group were approximately 1.78 and 1.65 times higher than those in the normoxia group, respectively (both P < 0.05).
CONCLUSION: The hypoxic environment at high altitudes can promote the metabolism of phenytoin sodium, reduce its absorption efficiency, and change the characteristics its distribution in the brain, which may be related to the up-regulation of the expression of CYP2C9 in the liver and that of P-gp in the brain.