Effects Of Carbamazepine,Lamotrigine,and Stiripentol On The Plasma Concentrations Of Valproic Acid And Its Metabolites

Objective:Epilepsy is a common neurological disorder,which can cause patients to have poor quality of life and shortened life expectancy.Valproic acid（VPA）is a traditional antiepileptic drug commonly used in clinical practice.Its main metabolites in vivo are 2-propyl-2-pentenoic acid（2-ene-VPA）,2-propyl-4-pentenoic acid（4-ene-VPA）,and valproic acid-O-glucuronide（VPA-G）.In clinic,valproic acid is often combined with carbamazepine（CBZ）,lamotrigine（LTG）and stiripentol（STP）in the treatment of epilepsy.However,the combination of drugs may cause drug interactions,resulting in reduced efficacy and even adverse reactions.The purpose of this study was to investigate the effects of CBZ,LTG and STP on the plasma concentrations of VPA and its metabolites（2-ene-VPA,4-ene-VPA and VPA-G）,so as to provide sufficient reference for the dose adjustment of multi-drug combination in the future.Methods:Twenty-four male SD rats were randomly divided into 4groups with 6 rats in each group and given intragastric administration.Group1 was given 200 mg·kg^-1VPA（VPA single group）,group 2 was given 200mg·kg^-1VPA+50 mg·kg^-1 CBZ（VPA+CBZ group）,group 3 was given 200mg·kg^-1VPA+10 mg·kg^-1 LTG（VPA+LTG group）,group 4 was given 200mg·kg^-1VPA+300 mg·kg^-1 STP（VPA+STP group）.The concentrations of VPA and its metabolites（2-ene-VPA,4-ene-VPA and VPA-G）in rat plasma were determined by HPLC-MS/MS.The pharmacokinetic parameters of VPA and its metabolites（2-ene-VPA,4-ene-VPA and VPA-G）were calculated by Graphpad Prism 8.0.2.263 software.Results:In this experiment,the chromatographic peak area of VPA metabolites（2-ene-VPA,4-ene-VPA and VPA-G）was used to replace the concentration of VPA metabolites（2-ene-VPA,4-ene-VPA and VPA-G）for analysis.The main pharmacokinetic parameters of VPA in these four groups:C_max were（27.27±8.10）μg·m L^-1,（16.95±4.65）μg·m L^-1,（28.25±7.34）μg·m L^-1 and（52.26±24.50）μg·m L^-1,t_maxwere（0.31±0.16）h,（0.18±0.09）h,（0.18±0.09）h and（0.29±0.10）h,AUC_0-24hwere（59.31±10.08）μg·m L^-1·h,（58.18±14.48）μg·m L^-1·h,（67.15±8.23）μg·m L^-1·h and（100.76±22.08）μg·m L^-1·h;The main pharmacokinetic parameters of 2-ene-VPA in these four groups:C_max（peak area）were（1.02×10⁷±1.58×10⁶）,（9.99×10⁶±1.64×10⁶）,（1.278×10⁷±2.30×10⁶）and（2.05×10⁷±3.90×10⁶）,t_max were（1.67±0.52）h,（1.00±0.01）h,（1.00±0.01）h and（1.17±0.41）h,AUC_0-24h（peak area）were（8.26×10⁷±1.77×10⁷）,（9.96×10⁷±2.25×10⁷）,（1.16×10⁸±2.64×10⁷）and（1.28×10⁸±6.59×10⁷）;The main pharmacokinetic parameters of 4-ene-VPA in these four groups:C_max（peak area）were（2.35×10⁶±4.02×10⁵）,（1.60×10⁶±3.19×10⁵）,（1.88×10⁶±4.55×10⁵）and（3.84×10⁶±1.20×10⁶）,t_maxwere（0.90±0.22）h,（1.00±0.01）h,（0.80±0.27）h and（1.00±0.01）h,AUC_0-24h（peak area）were（1.40×10⁷±2.81×10⁶）,（2.02×10⁷±2.58×10⁶）,（2.22×10⁷±2.59×10⁶）and（1.96×10⁷±1.38×10⁶）;The main pharmacokinetic parameters of VPA-G in these four groups:C_max（peak area）were（1.57×10⁸±1.96×10⁷）,（5.15×10⁷±1.94×10⁷）,（1.19×10⁸±3.27×10⁷）and（3.02×10⁸±1.23×10⁸）,t_max were（0.90±0.22）h,（0.50±0.01）h,（0.50±0.01）h and（0.92±0.20）h,AUC_0-24h（peak area）were（3.76×10⁸±5.58×10⁷）,（2.40×10⁸±4.58×10⁷）,（2.92×10⁸±1.94×10⁷）and（5.61×10⁸±1.37×10⁸）.Conclusions:When VPA was combined with CBZ,the peak concentration of VPA and its metabolite VPA-G decreased significantly,the AUC_0-24h of 4-ene-VPA increased markedly,and the AUC_0-24h of VPA-G decreased considerably.When VPA was used in combination with LTG,the peak concentration of VPA and its metabolites（2-ene-VPA,4-ene-VPA,and VPA-G）remained unchanged,while the AUC_0-24h of 4-ene-VPA and2-ene-VPA increased remarkably.When VPA was combined with STP,the peak concentration of VPA and its metabolites（2-ene-VPA,4-ene-VPA,and VPA-G）increased considerably.The AUC_0-24h of VPA and its metabolites（2-ene-VPA,4-ene-VPA,and VPA-G）increased remarkably.The experimental results can provide reference for the dose adjustment of VPA combined with CBZ,LTG and STP in the treatment of epilepsy in the future:When VPA is combined with CBZ,the dosage of VPA should be adjusted more carefully.When VPA is used in combination with LTG,the dosage of VPA should remain unchanged.When VPA is used in combination with STP,it is recommended that the dose of VPA be appropriately down-regulated.