摘要
第一部分CYP3A4*1G, CYP3A5*3, CYP3A4*18/*19基因多态性在卡马西平治疗的中国汉族癫痫患者中的分布
目的：观察CYP3A4*1G,CYP3A5*3, CYP3A4*18/*19基因多态性在卡马西平治疗的中国汉族癫痫患者中的分布和基因频率。
方法：选取247例卡马西平治疗(单药或与丙戊酸钠联合治疗)的中国汉族癫痫患者,提取患者外周血DNA,连接酶检测-聚合酶链反应(ligase detection reaction-Polymerase Chain Reaction, LDR-PCR)测序分型检测CYP3A4*1G,CYP3A5*3, CYP3A4*18/*19基因型。
结果：247例癫痫患者中有10例(4.05%)CYP3A4*1G基因AA型,92例(37.25%)AG型,145例(58.70%)GG型,A等位基因频率为22.67%,G等位基因频率为77.33%。CYP3A5*3基因AA型23例(9.31%),AG型109例(44.13%),GG型115例(46.56%),A等位基因频率为31.38%,G等位基因频率为68.62%。所有患者CYP3A4*18/*19基因都表现为CC型。
结论：中国汉族癫痫患者的CYP3A4*1G、CYP3A5*3基因多态性分布情况与其他亚洲人群类似。
第二部分中国汉族癫痫患者中CYP3A4*1G、YP3A5*3基因多态性与卡马西平药物浓度的相关性研究
目的：观察CYP3A4*1G、CYP3A5*3基因多态性与中国汉族癫痫患者卡马西平稳态药物浓度的相关性。
方法：应用反向高效液相色谱法检测247例卡马西平治疗的中国汉族癫痫患者的稳态谷值药物浓度,LDR-PCR测序分型检测CYP3A4*1G,CYP3A5*3基因多态性。
结果：总和组(所有247例患者)中CYP3A4*1G基因AA型的卡马西平标准化浓度为0.23±0.065μg·kg·(ml·g)-1,AG型为0.25±0.065μg·kg·(m1·g)-1,GG型为0.28±0.074μg·kg·(m1·g)-1。三基因型间标准化浓度差异有统计学意义(P=0.005),且AA型低于GG型(P=0.021),AG型低于GG型(P=0.009),差异均有统计学意义,AA型虽有低于AG型的趋势,但差异无统计学意义(P=0.220)。CYP3A5*3基因AA型的卡马西平标准化浓度为0.23±0.06μg·kg·(ml·g)-1, AG型为0.24±0.053μg·kg·(ml·g)-1,GG型为0.31±0.073μg·kg·(ml·g)-1。三基因型间标准化血药浓度差异有统计学意义(P<0.0001),且AA型低于GG型(P<0.0001),AG型低于GG型(P<0.0001),差异均有统计学意义,AA型虽有低于AG型趋势,但差异无统计学意义(P=0.087)。单药组(卡马西平单药治疗)结果与总和组类似,CYP3A4*1G和CYP3A5*3三基因型组间标准化血药浓度差异均有统计学意义(P<0.05),且AA型和AG型均显著低于GG型(P<0.05), AA型虽有低于AG型的趋势,但差异无统计学意义(P>0.05)。但联合用药组(卡马西平+丙戊酸钠联合治疗)中上述基因型间标准化浓度无显著性差异。
结论：CYP3A4*1G和CYP3A5*3基因型影响中国汉族癫痫患者的卡马西平药物浓度,是造成卡马西平药物浓度个体差异的可能因素。
第三部分中国汉族癫痫患者中CYP3A4*1G、CYP3A5*3基因多态性与卡马西平疗效的相关性研究
目的：研究CYP3A4*1G、CYP3A5*3基因多态性与中国汉族癫痫患者卡马西平疗效的相关性。
方法：检测245例卡马西平治疗的中国汉族癫痫患者外周血CYP3A4*1G、 CYP3A5*3基因多态性,根据基因表现型分为高代谢组(AA型和AG型)和低代谢组(GG型)。抗癫痫治疗6个月后评估疗效,根据发作频率减少情况分为显效(发作频率减少>75%),无效(发作频率减少<50%)和有效(发作频率减少介于50%和75%之间)三组。
结果：单因素分析发现,总和组中CYP3A4*1G基因高代谢组标准化血药浓度为0.25±0.067μg·kg·(ml·g)-1,显效率为36%,均显著低于低代谢组标准化浓度(0.28±0.080μg·kg·(ml·g)-1)和显效率(48.97%)(P<0.05),而高代谢组无效率(25%)显著高于低代谢组(18.62%)(P<0.05)。单药组结果与总和组类似,但联合用药组中不同CYP3A4*1G表现型间标准化浓度、显效率和无效率间差异无统计学意义(P>0.05)。总和组、单药组和联合用药组中CYP3A5*3GG型的显效率分别为63.48%,60.76%,69.44%,显著高于AG型(30.28%,,36.14%,38.16%)和AA型(4.76%,7.69%,38.16%),差异均有统计学意义(P<0.05),即GG型显效率最高,AA型最低,AG型居中。Logistic回归分析表明CYP3A4*1G基因表现型与疗效无关,而CYP3A5*3基因型是造成中国汉族癫痫患者卡马西平疗效个体差异可能的影响因素。
结论：CYP3A5*3基因型与卡马西平疗效有关,CYP3A5*3基因GG型标准化浓度高,显效率高,无效率低。
Part1:Single nucleotide polymorphisms and genotype frequencies of CYP3A4*1G, CYP3A5*3, CYP3A4*18/*19in Han Chinese epileptic patients
Objective To explore the distribution and genotype frequencies of CYP3A4*1G, CYP3A5*3, CYP3A4*18/*19in Han Chinese epileptic patients with carbamazepine(CBZ)-therapy.
Materials and Methods The CYP3A4*1G,CYP3A5*3, CYP3A4*18/*19genotype was determined by ligase detection reaction-Polymerase Chain Reaction (LDR-PCR) in247Han Chinese epileptic patients with carbamazepine (CBZ)-therapy.
Results Ten patients(4.05%) were AA allele of CYP3A4*1G,92(37.25%) were AG allele and145(58.70%) were GG allele. A allele frequencies were22.67%, while G allele frequencies were77.33%. Twenty-three patients (9.31%) were AA allele of CYP3A5*3,109patients (44.13%) were AG allele, and115patients (46.56%) were GG allele. And A allele frequencies were31.38%, G allele frequencies were68.62%. All patients were CC allele of CYP3A4*18/*19.
Conclusion The genotype frequencies of CYP3A4*1G and CYP3A5*3in Han Chinese epileptic patients is similar to it in other Asian population.
Part2:Effect of CYP3A4*1G, CYP3A5*3genotype on serum carbamazepine concentrations at steady-state in Han Chinese epileptic patients
Objective The present study aimed to assess the effect of CYP3A4*1G, CYP3A5*3genotype on serum CBZ concentrations at steady-state.
Materials and Methods The serum concentrations of CBZ in247Han Chinese epileptic patients with CBZ-therapy and their CYP3A4*1G, CYP3A5*3genotype was determined by LDR-PCR method.
Results Among all247Han Chinese epileptic patients(total group), the normalized concentrations of CBZ were0.23±0.065μg·kg·(ml·g)-1) for CYP3A4*1G AA allele,0.25±0.065μg·kg·(ml·g)-1) for AG allele and0.28±0.074μg·kg·(ml·g)-1) for GG allele. There was a significant difference between these three different genotypes (P=0.005).And the normalized concentrations of both AA allele and AG allele were lower than those of GG allele, and the difference was statistical significance(P<0.05). Although the normalized concentrations of AA allele were lower than those of AG allele, there was no significant difference between them. They were0.23±0.066μg·kg·(ml·g)-1) for CYP3A5*3AA allele,0.24±0.053μg·kg·(ml·g)-1) for AG allele and0.31±0.073μg·kg·(ml·g)-1) for GG allele. There was a significant difference between these three different genotypes (P<0.0001). The normalized concentrations of CBZ were significant higher in GG allele. But there was no significant difference between AA allele and AG allele. The same result was found in monotherapy group but not in add-on group.
Conclusion The CYP3A4*1G, CYP3A5*3genotype affected the CBZ concentrations in Han Chinese patients that the normalized concentrations of CBZ in patients of GG allele were higher. And it is a possible factor that may contribute to inter-individual variability in CBZ disposition in Han Chinese epileptic patients.
Part3:Influence of CYP3A4*1G, CYP3A5*3genotype on carbamazepine efficacy in Han Chinese epileptic patients
Objective To investigate the relationship between the CYP3A4*1G CYP3A5*3genotype and the CBZ treatment outcome in Han Chinese epileptic patients.
Materials and Methods The CYP3A4*1G CYP3A5*3genotype was determined in245Han Chinese epileptic patients with CBZ-therapy (including total group, monotherapy group and add-on group). Then they were also classified by phenotype of CYP3A4*1G CYP3A5*3gene as the hypermetabolism group (AA allele and AG allele) and the hypometabolism group (GG allele). The efficacy at6months after therapy were classified as markedly effective (the reduction of seizure frequency>75%), effective (50% Results In total group, both the normalized concentrations (0.25±0.067μg·kg·(ml·g)-1) and the markedly effective rates (36%) of CYP3A4*1G hypermetabolism group, were significant higher than the hypometabolism group (0.28±0.080μg·kg·(ml·g)-1)(48.97%)(P<0.05). While the ineffective rates of hypermetabolism group (25%) were significant higher than the hypometabolism group (18.62%)(P<0.05). The same result was found in monotherapy group but not in add-on group. The markedly effective rates of CYP3A5*3GG allele were63.48%,60.76%,69.44%, in total group, monotherapy group, and add-on group, which were significant higher than those in AG allele(30.28%,36.14%,38.16%) and AA allele(4.76%,7.69%,38.16%). And it showed in Logistic Regression that the CYP3A4*1G genotype had no influence on the CBZ efficacy. But the CYP3A5*3genotype was possible factor that may contribute to inter-individual variability in CBZ efficacy in Han Chinese epileptic patients in Logistic Regression analysis.
Conclusion The CYP3A5*3genotype had influence on the carbamazepine concentrations and efficacy. The normalized concentrations and markedly effective rates of CYP3A5*3GG allele were significant higher.
引文
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[1]Depondt C, Godard P, Espel RS et al. A CANDIDATE GENE ASSOCIATION STUDY OF ANTIEPILEPTIC DRUG TOLERABILITY AND EFFICACY [J]. Epilepsia 2010,51(2):143-143.
[2]Ingelman-Sundberg M, Sim SC. Pharmacogenetic biomarkers as tools for improved drug therapy; emphasis on the cytochrome P450 system [J]. Biochemical and Biophysical Research Communications,2010,396(1):90-94.
[3]中华医学会.临床诊疗手册-癫痫病分册[M].北京：人民卫生出版社,2007：41.
[4]洪震,江澄川.现代癫痫学[M].北京：人民卫生出版社,2007：97—109.
[5]朱国行,吴洵昳,虞培敏等.新诊断癫痫患者的规范化药物治疗[J].中华神经科杂志,2011,44(1)：6-9.
[6]Kato M, Chiba K, Ito T et al. Prediction of Interindividual Variability in Pharmacokinetics for CYP3A4 Substrates in Humans [J]. Drug Metabolism and Pharmacokinetics,2010,25(4):367-378.
[7]Caligula L, Viana M, Fallarini S et al. Possible impact of CYP3A4 and CYP3A5 genotypes on carbamazepine metabolism and clinical outcome in epileptic patients[J]. Febs Journal,2010,277:289-290.
[8]Depondt C. Pharmacogenetics in epilepsy treatment:sense or nonsense [J]? Personalized Medicine,2008,5(2):123-131.
[9]Zhang W, Chang Y-Z, Kan Q-C et al. CYP3A4*1G genetic polymorphism influences CYP3A activity and response to fentanyl in Chinese gynecologic patients [J]. European Journal of Clinical Pharmacology,2011,66(1):61-66.
[10]文娟,黄志军,袁洪等.肾移植后高血压人群中CYP3A4*1G、CYP3A5*3和MDR1C3435T基因多态性对氨氯地平降压疗效的影响[J].中国动脉硬化杂志,2011,19(1)：55-60.
[11]McLeod HL, Watson MA. Editorial overview-Molecular therapeutics:Are we making progress [J]? Current Opinion in Molecular Therapeutics,2003, 5(6):573-574.
[12]. Andreasen AH, Brosen K, Damkier P. A comparative pharmacokinetic study in healthy volunteers of the effect of carbamazepine and oxcarbazepine on CYP 3A4 [J]. European Neuropsychopharmacology,2006,16:239.
[13]. Park PW, Seo YH, Ahn JY et al. Effect of CYP3A5*3 genotype on serum carbamazepine concentrations at steady-state in Korean epileptic patients [J]. Journal of Clinical Pharmacy and Therapeutics,2009,34(5):569-574.
[14]胡永芳,翟所迪,邱雯CYP3A5*3和CYP3A4*18B基因多态性对肾移植患者环孢素药代动力学的影响[J].中国药理学通报,2009,25(3)：378-382.
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