| Summary: | 碩士 === 中國醫藥大學 === 藥學系碩士班 === 99 === Valproic acid is one of the most widely used antiepileptic drugs (AEDs) for treatment of both partial and generalized seizures either in monotherapy or in combination with other AEDs in adults and children. However, for a given dose, there were large differences between individuals in response to valproic acid due to a broad recommended dose range and a wide effective therapeutic plasma level (50–100 mg/L). There were some SNPs at genes that involved in valproic acid mechanism of action, disposition or metabolism, and this substitution might affect the antiepileptic effect of valproic acid. The aims of this study are to evaluate the effect of genetic polymorphisms on valproic acid serum concentration, daily dosage or concentration to dose ratio (CDR) and better individualize the medication for patients with epilepsy.
190 healthy control subjects and 162 epileptic patients treated with valproic acid were recruited from the department of Neurology of National Taiwan University Hospital (NTUH). Blood samples for genotyping were collected after informed consents were obtained from all subjects.The polymerase chain reaction (PCR) - restriction fragment length polymorphism (RFLP) and Real-Time PCR were applied to analyze the 14 single nucleotide polymorphisms (SNPs) in the candidate genes: UGT1A6, UGT1A9, UGT2B7, FABP2, GRIN2B, ABAT and GABRA5.
The mean dose of valproic acid was 1197.45±43.47mg and the mean serum concentration was 68.81±1.94mg/L. The results demonstrated that patients with the variant genotypes in GRIN2B −200T>G required significant lower effective doses of valproic acid and higher CDRs than those with wild-types (all p<0.0001). On the other hand, the effective doses of valproic acid were higher and CDRs were lower in patients with the variant genotypes in UGT1A6 c.19T>G, c.541A>G and c.552A>C respectively (all p<0.0001). Moreover, the haplotype and haplotype combinations analyses also revealed that haplotypes composed of GRIN2B -200T>G and -421C>A were significantly associated with doses and CDRs of valproic acid (p<0.0001). And haplotype and haplotype combinations composed of UGT1A6 c.19T>G, c.541A>G, c.552A>C and UGT1A9 I399T>C, -1887T>G were significantly associated with doses or CDRs of valproic acid (p<0.0001). Furthermore, in the multiple regression model, the combined effect of UGT2B7 c.802T>C, -161C>T and -842A>G was demonstrated to be correlated with the dosage and CDRs of valproic acid in proportional odds regression model (adjusted R2 = 0.71 and 0.47, respectively).
In conclusion, this study suggests that polymorphisms in several genes encoding for drug targets and metabolizing enzymes were associated with valproic acid dosage and CDR. The polymorphisms in GRIN2B, UGT1A6 and UGT2B7 genes may explain a part of the interindividual variability in valproic acid treatment. Further larger population studies are required to confirm our findings.
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