| 摘要: | Valproic acid 之抗癲癇作用是目前市面上所有抗癲癇藥物當中最廣效的一個，可單獨使用或併用其他抗癲癇藥物治療成人與兒童的全身性發作及部分發作。但是，valproic acid的建議劑量範圍很大且有效治療之血中濃度也很廣泛 (50–100 mg/L)，服藥後的個體間差異性很大。而參與valproic acid作用、分布及代謝的基因上，曾有許多研究指出，基因上的單核苷酸多型性可能會影響其抗癲癇作用。因此，本研究目的為，探討藥物動力學及藥物效力學兩個路徑上的基因多型性與癲癇病患使用的valproic acid治療劑量、血中藥物濃度和濃度與劑量比值間之相關性，應用於癲癇患者的個人化藥物治療，提供更安全有效的用藥環境。
從台灣大學附設醫院共收納服用valproic acid之癲癇病患162人，以及過去未曾罹患癲癇疾病的健康受試者共190人，且所有供基因型分析的血液樣本，皆是於受試者簽署試驗同意書後取得。利用Polymerase chain reaction (PCR)–restriction fragment length polymorphism (RFLP) 和 Real-time PCR來分析分別位於不同目標基因(包含UGT1A6、UGT1A9、UGT2B7、FABP2、GRIN2B、ABAT與GABRA5)上的14個位點。
患者服用valproic acid的平均劑量為1197.45±43.47mg，而valproic acid之平均穩定狀態血中濃度為68.81±1.94mg/L。結果顯示，GRIN2B -200T>G此位點，基因型為變異型的病患較基因型為野生型的人更傾向於服用低劑量的valproic acid且濃度與劑量比值較高(p<0.0001)；而基因多型位點UGT1A6 c.19T>G、c.541A>G和c.552A>C，若基因型為變異型者，則是傾向於服用較高劑量的valproic acid且濃度與劑量比值較低(p<0.0001)。此外，(GRIN2B -200T>G)-(GRIN2B -421C>A)這兩個基因多型性位點的單套型與單套型組合以及(UGT1A6 c.19T>G)-(UGT1A6 c.541A>G)-(UGT1A6 c.552A>C)-(UGT1A9 I399T>C)-(UGT1A9 -1887T>G) 這五個基因多型性位點的單套型與單套型組合，也與患者的valproic acid劑量和濃度與劑量比值有顯著相關(p<0.0001)。在模式分析中，考慮癲癇類型與併服的其他抗癲癇藥物後，UGT2B7 c.802T>C、-161C>T和-842A>G也與患者所服用的valproic acid劑量和濃度與劑量比值有相關性(adjusted R2分別為0.71與 0.47)。
總結來說，本研究發現，在藥物作用受體與代謝酵素上的基因多型性與valproic acid的服用劑量及濃度與劑量比值間存在相關性，而GRIN2B、UGT1A6與UGT2B7上的基因多型性可能是造成服用valproic acid後個體間差異性的主要因素之一。未來仍需更大的族群研究以證實我們的發現。
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. |
