Effect of high altitude on the pharmacokinetics and pharmacodynamics of valproate in epileptic rats.

Background: Valproate (VPA) is one of the most widely used drugs for epilepsy. However, it has a narrow therapeutic window and exhibits significant inter-individual variability. Previous studies have suggested that under high altitude conditions, VPA absorption increases and its metabolism slows in healthy rats, indicating that environmental factors can substantially alter its pharmacokinetic (PK) behavior. Nevertheless, it remains unclear how high altitude affect VPA metabolism and efficacy under pathological conditions, such as epilepsy. Objective: This study aimed to investigate the effects of high altitude on the PK and pharmacodynamics (PD) of VPA in epileptic rats, providing experimental evidence for individualized medication in epilepsy patients rapidly entering high altitude regions. Method: We prepared the epilepsy model by using the lithium chloride-pilocarpine method. Epileptic rats were randomly assigned to the epileptic + VPA (EV) group and the EV + high altitude (EVH) group for the PK and brain distribution study. VPA concentrations were quantified using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and PK parameters were calculated. The expression of P-glycoprotein (P-gp) and hypoxia-inducible factor-1α (HIF-1α) in the blood-brain barrier (BBB) was assessed by Western blot. For the PD study, twenty-four epileptic rats were divided into four groups, including epileptic (E) group, E + high altitude (EH) group, EV group and EVH group. PD effects were evaluated by monitoring seizure scores and the number of seizures. Subsequently, oxidative stress and inflammatory cytokines in brain were measured. Results: High altitude significantly alters the PK behavior and PD of VPA. Compared with the EV group, EVH group showed lower plasma concentrations, reduced area under the curve, increased clearance, and shorter mean residence time. Meanwhile, the expression of HIF-1α and P-gp in the BBB was significantly up-regulated in the EVH group. PD studies revealed high altitude increased seizure scores and frequency, along with exacerbated oxidative stress and inflammation. Conclusion: High altitude not only exacerbate seizure severity but also significantly alter the PK and PD of VPA in epileptic rats. This study suggests that epilepsy patients rapidly entering high altitude regions may require an appropriate increase in dosage and enhanced PK/PD monitoring during VPA treatment to ensure clinical efficacy.