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Valproic acid (VPA), an anti-epileptic drug with a narrow therapeutic index, is a substrate of the monocarboxylate transporter (MCT). In this study, we investigated the effect of Gegen-Qinlian-Tang (GQT), a Chinese Medicine prescription containing Puerariae Radix (PR), Scutellariae Radix (SR), Coptidis Rhizoma (CR) and Glycyrrhizae Radix (GR), on the pharmacokinetics of VPA, as a probe drug of MCT, in rats and the underlying mechanism. Sprague-Dawley rats were orally administered VPA with and without GQT in crossover design. The serum concentrations of VPA were determined by a fluorescence polarization immunoassay. The results showed that coadministration with 2.0 and 4.0 g/kg of GQT remarkably decreased the Cmax of VPA by 72% and 74% and reduced the AUC 0-t by 63% and 53%, respectively. The mechanism study using Caco-2 cells revealed that the uptake function of MCT was inhibited by GQT and each component herb. In conclusion, the MCT-mediated absorption of VPA was significantly decreased by GQT and its component herbs.

Aim: The present study aimed to investigate the associations between variants in pharmacokinetic- and pharmacodynamic-related genes with the dosages, concentrations and concentration-dose ratios (CDRs) of phenytoin (PHT)., Methods & Results: Eleven genetic polymorphisms in the six candidate genes were detected in 269 epileptic patients under maintenance PHT monotherapy by real-time PCR and PCR-RFLP. Results of a bivariate analysis demonstrated that among tested polymorphisms, carriers of the variant CYP2C9*3 tended to require significantly lower maintenance PHT dosages than wild-type carriers (p < 0.0001); on the other hand, carriers of the variants CYP2C9*3 or CYP2C19*3 revealed significantly higher CDRs than wild-type carriers (p < 0.004). In a further multivariate analysis, variants in SCN1A, CYP2C9, CYP2C19 and ABCB1 genes were significantly associated with CDRs of PHT under adjustment of age, gender and epilepsy classifications (adjusted r(2) = 20.07%)., Conclusion: The results of present study indicated that polygenic analysis may provide useful information in PHT therapy optimization.

Aim: Carbamazepine (CBZ) is one of the most widely used antiepileptic drugs. The aim of the present study is to investigate the impacts of polymorphisms in genes related to pharmacokinetic and pharmacodynamic pathways of CBZ on the large interindividual variability in dosages and concentrations., Methods & Results: Genetic polymorphisms in the candidate genes were detected in 234 epileptic patients under maintenance CBZ monotherapy by real-time PCR and PCR-RFLP. Results of statistical analysis demonstrated that carriers of the variant SCN1A IVS5-91G>A and EPHX1 c.337T>C allele tended to require higher CBZ dosages and lower ln(concentration-dose ratios) than noncarriers (p < 0.0001) and the homozygous carriers also seemed to require higher CBZ dosages and lower ln(concentration-dose ratios) (p < 0.0001). In addition, the multiple regression model of concentration-dose ratio of CBZ also revealed that genetic variants in SCN1A, EPHX1 and UGT2B7 genes interactively affect the concentration-dose ratio of CBZ (adjusted r(2) = 55%)., Conclusion: The present study identified genetic factors associated with CBZ therapy optimization and provided useful information for individualized CBZ therapy in epileptic patients. Further studies in larger populations are needed to confirm our results.

Aims: Valproic acid (VPA) is one of the most widely used antiepileptic drugs. The aim of the study was to investigate whether polymorphisms in genes related to pharmacokinetic and pharmacodynamic pathways of VPA were associated with the large interindividual variability in dosages and concentrations., Methods & Results: Genetic polymorphisms in six candidate genes were detected in 162 epileptic patients under maintenance with VPA monotherapy and stable seizure control by real-time PCR and PCR-RFLP. Results of statistical analysis demonstrated that carriers of the variant UGT1A6 19T>G, 541A>G and 552A>C allele tended to require higher VPA dosages and lower ln(concentration-to-dose ratios [CDRs]) than noncarriers (p < 0.0001) and the homozygous carriers also seemed to require higher VPA dosages and lower lnCDRs (p < 0.0001). On the other hand, carriers of the variant GRIN2B -200T>G allele were more likely to require lower VPA dosages than noncarriers (p < 0.0001) and the homozygous carriers also tended to require lower dosages and higher lnCDRs (p < 0.0001). In addition, the regression model of CDR of VPA also revealed that genetic variants in UGT1A6, GRIN2B and UGT2B7 genes interactively affect CDRs of VPA (adjusted r² = 47%)., Conclusion: Although there was a limited sample size, the study identified genetic factors associated with VPA therapy optimization that has not been revealed, and provided useful information for individualized VPA therapy in epileptic patients.