| Summary: | 碩士 === 中國醫藥大學 === 藥學系碩士班 === 99 === Carbamazepine is a widely prescribed antiepileptic drug (AED) with narrow therapeutic index. The genetic effect on interindividual variations of dosage of carbamazepine was not well understood. The aim of the present study was to investigate the association between the variants in pharmacokinetics and pharmacodynamics related genes and the carbamazepine dosage requirement, serum concentration and concentration to dose ratio (CDR).
189 Healthy control subjects and 234 patients treated with carbamazepine were recruited from the department of Neurology of National Taiwan University Hospital (NTUH), and the daily dosage, serum concentration and CDR of carbamazepine was recorded. These patients were treated with carbamazepine over six months to achieve the maintenance dose. After signed informed consent, 10 ml blood was drawn to extract genomic DNA. 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: SCN1A, SCN2A, EPHX1, UGT2B7, ABCB1 and ABCC2.
Association tests were conducted among the genotypes and alleles of each polymorphism and the three dosage groups (<800 mg, 800-1199 mg and ≧1200 mg), mean serum concentration and two CDR groups (CDR≦10 ?尳-1and CDR >10 ?尳-1). The results demonstrated that SCN1A IVS5-91G>A and EPHX1 c.337C>T polymorphisms were significantly associated with the dose of carbamazepine and CDR. For SCN1A IVS5-91G>A, the patients with the variants genotypes and alleles were more likely to take a higher dose of carbamazepine and lower CDR compared with wild-type (all p<0.0001). For EPHX1 c.337T>C, the patients with variants genotypes and alleles were more likely to take a higher dose of carbamazepine and lower CDR compared with wild-type (all p<0.0001). Further haplotype and haplotype combination analyses also revealed that the haplotypes composed of SCN1A c.3184A>G – IVS5-91G>A were significantly associated with carbamazepine dose and CDR. Patients with the AA and GA haplotypes were more likely to take a higher dose of carbamazepine compared with AG haplotype (p<0.0001 and p=0.0030, respectively). Moreover, the patients with AA haplotype were more likely to have lower CDR compared with AG haplotype (p=0.0003). Besides, patients with AG/AA, AA/AA, AA/GG and AA/GA haplotype combinations were more likely to take the higher doses of carbamazepine compared with AG/AG haplotype combination (p=0.0441, <0.0001, 0.0214 and 0.0021, respectively). These associations remained significant after Bonferroni’s corrections. The proportional odds regression analyses were conducted under adjustment of confounding factors, such as epilepsy syndromes, etiology classifications and concomitant AEDs. The results indicated that factors co-medication of levetiracetam, SCN1A IVS5-91G>A, EPHX1 c.337T>C and the interaction terms of ABCB1 c.1236C>T and c.2677G>T/A significantly affected the dosage of carbamazepine (adjusted r2 = 0.71). On the other hand, the factors co-medication of phenytoin, lamotrigine, SCN1A IVS5-91G>A, EPHX1 c.337T>C and UGT2B7 c.802T>C significantly affected the CDR of carbamazepine (adjusted r2 = 0.37).
Our findings demonstrated that genetic variants in SCN1A IVS5-91G>A and EPHX1c.337T>C genetic polymorphisms may be associated with the dose and CDR of carbamazepine in treatment of epilepsy patients. The present study set the stage for a prospective evaluation of how pharmacogenomic results may be used to optimize the dose of carbamazepine in epileptic patients.
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