丙戊酸药物浓度与CYP2C19基因多态性关系的研究

目的：寻找丙戊酸药物浓度与CYP2C19基因多态性的关系，以便临床根据患者的基因型进行个体化给药。方法：运用血药浓度监测仪测定患者血药浓度和变性高效液相色谱法检测癫痫患者的CYP2C19基因多态性位点．对二者结果进行相关性分析。结果：51名汉族癫痫患者中有29名携带突变型CYP2C19基因，其中19名(65．52％)患者丙戊酸实际血药浓度较预期的血药浓度升高，血药浓度分布曲线右移。结论：CYP2C19参与丙戊酸的代谢。对于含突变型CYP2C19基因的患者应给予小剂量丙戊酸，以减少药物不良反应的发生和药物资源的浪费。     

CYP2C19基因多态性对癫痫患者丙戊酸血药浓度的影响

目的：研究癫痫患者CYP2C19基因多态性与丙戊酸稳态血药浓度的关系。方法：运用PCR-RFLP方法对99例癫痫病人的CYP2C19＊2（681G→A）和CYP2C19＊3（636G→A）位点进行基因型分析,选择其中临床资料较全的88名,对其丙戊酸血药浓度检测结果与基因型结果进行统计学分析。结果：在99例患者中,同时分析两个位点共5种双位点基因型组合：681GG-636GG、681GA-636GG、681GG-636GA、681AA-636GG和681GA-636GA,分布频率为37.4%、42.4%、6.1%、9.1%和5.1%。其中681AA-636GG基因型患者的丙戊酸血药浓度与体重剂量的比值明显高于野生基因型（681GG-636GG）（P〈0.05）,其他基因型与野生型相比无统计学差异。结论：本研究结果证实CYP2C19基因多态性影响了丙戊酸血药浓度,说明药物遗传学研究对丙戊酸临床合理用药有指导意义。     

癫痫患者CYP2C19基因多态性分析

目的研究癫痫患者CYP2C19基因多态性。方法运用PCR-RFLP方法对67例应用丙戊酸的癫痫患者的CYP2C19＊2和CYP2C19＊3位点进行基因型分析。结果两个位点共有5种基因型组合：681GG-636GG、681GA-636GG、681GG-636GA、681AA-636GG、681GA-636GA。快代谢者（EMs）包括681GG-636GG、681GA-636GG、681GG-636GA基因型,分布频率为86．57％;慢代谢者（PMs）包括681AA-636GG、681GA-636GA基因型,分布频率为13．43％。结论PMs发生率与国内报道相近,CYP2C19基因多态性分析有助于丙戊酸的临床合理应用。。     

苯妥英钠血药浓度与CYP2C19基因多态性关系的研究

目的:探讨苯妥英钠药物浓度与CYP2C19基因多态性的关系,以指导临床个体化用药.方法:运用血药浓度监测仪测定患者血药浓度和变性高效液相色谱法检测癫痫患者的CYP2C19基因多态性位点,对二者结果进行相关性分析.结果:21例中国汉族癫痫患者中有12例含突变型CYP2C19基因.在7例(58.33%)苯妥英钠血药浓度的比值高于剂量比值的患者中,6例(85.7%)为突变型基因携带者(慢代谢者).结论:CYP2C19是苯妥英钠的主要代谢酶.CYP2C19基因突变等位基因携带者苯妥英钠代谢减慢,应给予小剂量苯妥英钠,以减少药物不良反应的发生和药物资源的浪费.     

CYP2C19基因多态性对精神分裂症患者丙戊酸血药浓度的影响

目的 研究CYP2C19基因多态性与精神分裂症患者心境稳定剂丙戊酸血药浓度的关系。方法 选择奥氮平治疗且服用丙戊酸钠作为心境稳定剂的精神分裂症患者160例,采集血液,测定CYP2C19基因型以及丙戊酸血药浓度,比较各个基因型血药浓度的差异。结果 *2/*2型(122.06±41.30)mg·L^-1和*2/*3型(132.34±51.34)mg·L^-1患者丙戊酸血药浓度明显高于野生*1/*1型(79.41±25.14)mg·L^-1(P<0.05或P<0.01);*1/*1、*1/*2和*1/*3型之间、*2/*2和*2/*3型之间血药浓度无统计学差异;PM型血药浓度(122.13±42.85)mg·L^-1与EM型(80.59±48.60)mg·L^-1比较,显著升高(P<0.05)。 结论 *2/*2和*2/*3型CYP2C19患者,其血液丙戊酸浓度较高,该类患者服用丙戊酸作为精神分裂症心境稳定剂时,宜适当降低用药剂量。     

碳青霉烯类抗生素致丙戊酸血药浓度降低

目的 探讨影响丙戊酸体内代谢的危险因素,促进合理用药水平,降低癫痫复发率。方法 分析2例给予丙戊酸后,血药浓度监测结果均小于1 μg/ml的患者。临床药师查阅文献,从药物相互作用、肝药酶活性及基因多态性等多方面积极分析并查找相关原因。结果 2例患者联合使用碳青霉烯类抗生素与丙戊酸,且同时服用肝药酶诱导剂苯巴比妥或利福霉素钠,促进丙戊酸代谢。基因型检测发现2例患者均携带CYP2C19突变型等位基因,丙戊酸代谢能力为中等或慢代谢。提示药物相互作用和CYP450催化活性增强是丙戊酸血药浓度降低的主要原因。结论 在碳青霉烯类抗生素和丙戊酸合用时,临床医生应密切关注丙戊酸血药浓度和癫痫发作症状。     

UGT1A6、UGT1A9基因多态性对汉族癫痫患者丙戊酸血药浓度的影响

目的:考察尿苷二磷酸葡萄糖醛酸转移酶(UGT)1A6和1A9基因多态性对汉族癫痫患者丙戊酸血药浓度的影响。方法:选取2014年1月—2015年4月于我院门诊就诊的汉族癫痫患者107例,均使用丙戊酸单药治疗,治疗时间为3个月~6年。采用酶放大免疫法测定患者体内丙戊酸稳态血药浓度,采用基质辅助激光解吸电离飞行时间质谱法检测其UGT1A6(rs2070959、rs6759892)和UGT1A9(rs13418420、rs2741045、rs2741049、rs6731242、rs72551330)基因型,并考察基因多态性与丙戊酸标准化血药浓度(CDR)的相关性。结果:未检出UGT1A9 rs72551330突变型,其余6个位点基因型频率均符合Hardy-Weinberg平衡(P>0.05)。UGT1A6 rs2070959、rs6759892突变基因携带(AG+GG或TG+GG型)者丙戊酸CDR值显著低于其野生纯合子携带(AA或TT型)者,差异均有统计学意义(P<0.05);而携带UGT1A9 rs13418420、rs2741045、rs2741049和rs6731242野生纯合子和突变基因的患者丙戊酸CDR值比较,差异均无统计学意义(P>0.05)。结论:汉族癫痫患者UGT1A6 rs2070959、rs6759892基因多态性与丙戊酸血药浓度有关,且UGT1A6 rs2070959、rs6759892突变基因携带者可能需要更高的丙戊酸剂量。     

丙戊酸治疗小儿癫痫的效果及影响血药浓度的因素分析

目的：探讨丙戊酸治疗小儿癫痫的效果及影响血药浓度的因素分析。方法：回顾性分析2014年7月至2017年7月三家三甲医院儿科使用丙戊酸进行治疗的癫痫患儿312例。所有患儿均进行CYP2C19基因多态性检测,确定患儿的CYP2C19的基因类型。口服丙戊酸治疗10 d,待血药浓度稳定后进行血药浓度检测。结果：患儿治疗后显效125例（40.06%）,有效138例（44.23%）,总有效率为84.29%;平均血药浓度（44.59±27.60）μg/mL。6~11岁患儿平均血药浓度[（84.33±22.56）μg/mL]高于其他年龄段患儿。基因型EM的患儿144例（46.15%）,基因型IM的患儿70例（22.43%）,基因型PM（弱代谢）患儿98例（31.41%）。<3岁EM患儿血药浓度最低[（26.31±13.22）μg/mL],6~11岁PM患儿的血药浓度最高[（96.31±34.25）μg/mL]。结论：小儿癫痫使用丙戊酸治疗有效率84.29%,可以根据患儿的年龄和基因类型,合理调整治疗方案,达到最佳的治疗效果。     

中国人群癫痫患者CYP2C19、CYP2C9的基因型对丙戊酸清除率影响的研究

目的:阐明中国人群癫痫患者CYP2C19和CYP2C9的基因多态性对丙戊酸清除率的影响。方法:收集216例癫痫患者的一般生物学资料和临床常规监测的丙戊酸(VPA)稳态血药浓度(谷浓度)数据。提取血样中白细胞的DNA并进行PCR扩增,用限制性片断长度多态性技术(RFLP)分别检测CYP2C19和CYP2C9的基因型。依据不同的基因型。将病人分为3组:G1、G2和G3。G1组:野生型;G2组:突变杂合型;G3组:突变纯合型。分别求算3组患者稳态血药谷浓度与每日公斤体重药量的比值,即丙戊酸的清除率。采用多元回归分析法推算不同基因型对丙戊酸清除率的影响。结果:216例病人中,G_1、G_2、G_3组人数分别为86、86、44。3组患者稳态血药谷浓度分别为:(54.13±21.53)、(54.43±18.86)、(62.55±25.62)μg/mL;清除率分别为(11.49±4.47)、(11.13±4.95)、(9.40±4.67) mL·h~(-1)·kg~(-1)。每种基因型均和丙戊酸的清除率具有相关性。采用多元回归分析求得回归方程为:G1组:Y=7.395 0,299 mg·kg~(-1)·d~(-1);G2组:Y=4.503 0.473 mg~(-1)·kg~(-1)·d~(-1);G3组:Y=5.025 0.335 mg·kg~(-1)·d~(-1)。CYP2C19和CYP2C9的不同基因型对丙戊酸清除率的影响具有统计学意义且G3组患者的清除率明显低于G1组和G2组。结论:CYP2C19、CYP2C9的基因型对丙戊酸的清除率有影响,突变纯合型患者丙戊酸的清除率明显低于野生型和突变杂合型的患者,应依据基因型进行个体化用药。     

CYP2C19基因多态性与肝癌易感性关系的研究

目的 研究内蒙古地区汉族人群CYP2C19基因多态性与肝癌易感性的关系.方法 采用等位基因特异性扩增(ASA)技术对内蒙古地区254例汉族健康人和68例汉族肝癌患者进行CYP2C19基因型分布频率的研究,分析CYP2C19基因多态性与肝癌易感性的关系.结果 CYP2C19ml 3种多态基因型在内蒙古地区汉族人群肝癌组与对照组的分布频率分别为:wt/wt 50％、wt/ml 33.8％、ml/ml 16.2％和wt/wt 40.6％、wt/ml 50.3％、ml/ml9.1％.结果 显示携带CYP2C19ml突变杂合型(wt/ml)的个体患肝癌的风险度比野生型纯合子(wt/wt)升高1.8倍,经统计学检验差异有显著性(P＜0.05).CYP2C19m2基因型在内蒙古地区汉族人群肝癌组与对照组的分布频率分别为wt/wt 85.3％、wt/m2 14.7％和wt/wt 91.3％、wt/m2 8.7％,两者之间比较差异无统计学意义(P＞0.05).对照组中CYP2C19快代谢者占87％,慢代谢者占13％;肝癌组中快代谢者占72.1％,慢代谢者占27.9％,经统计学检验差异有显著性(P＜0.05).慢代谢型患肝癌的危险是快代谢型的2.6倍.结论 携带突变杂合型CYP2C19ml基因型者肝癌的易感性增加,CYP2C19慢代谢型与肝癌的风险有关.     

UGT1A6基因多态性与癫痫患者丙戊酸血药浓度相关性研究

目的：探讨尿苷二磷酸葡萄糖醛酰转移酶（UGT）1A6基因多态性对癫痫患者丙戊酸血药浓度的影响。方法：对40例癫痫患者应用限制性酶切片段多态性技术分析中国汉族人常见的UGT1A6552A＞C等位基因变异,应用荧光偏振免疫法测定患者丙戊酸的血药浓度,在进行标准化以排除剂量和体重对血药浓度的影响后,分析不同UGT1A6基因型患者丙戊酸血药浓度的差异。结果：UGT1A6552A＞C等位基因频率为0.2625,符合Hardy-Weinberg平衡。将患者分为 AA野生纯合子型慢代谢组和AC合并AA突变型快代谢组,慢代谢组的丙戊酸标准化血药浓度显著高于快代谢组（P＜0.01）。结论：UGT1A6552A＞C基因多态性与丙戊酸的血药浓度有相关性,该位点突变可导致丙戊酸血药浓度降低。     

Influence of CYP2C9 polymorphism on metabolism of valproate and its hepatotoxin metabolite in Iranian patients

Sodium valproate (VPA) has 16 known metabolites in humans. The 2-ene-VPA has anti-convulsant efficacy and 4-ene-VPA is reported to contribute in VPA hepatotoxicity. The formation of 4-ene-VPA is catalyzed by cytochrome P450 2C9 (CYP2C9). CYP2C9 allele mutation is closely related to the attenuation of the enzymatic activity and 4-ene-VPA production. In the present work, VPA, 2-ene-VPA, and 4-ene-VPA in serum of patients receiving VPA were determined and the correlation between CYP2C9 polymorphism and 4-ene-VPA concentration was examined. Blood samplings in 68 patients were performed at two time-points (peak and trough) and one sample blood obtained from 50 healthy volunteers for genotype evaluation. Patients were divided into three groups (22 cases of monotherapy, 19 cases of enzyme inducer therapy, and 27 cases of polytherapy). There was a significant reduction in concentration of VPA and 4-ene-VPA between peak and trough time. In peak concentration, there was a significant correlation between 2-ene-VPA and VPA in all groups. The concentration of 4-ene-VPA in the enzyme inducer and polytherapy group was significantly higher than that of the monotherapy group. The allele frequencies of CYP2C9*1, CYP2C9*2, and CYP2C9*3 were 88.97%, 8.09%, and 2.94% in the patient group and 91%, 6%, and 3% in the normal group, respectively. There was no significant difference in allele frequency in two groups. Mutated alleles didn’t have any significant effect on 4-ene-VPA production. No patient showed toxic level of 4-ene-VPA or saturation of ß-oxidation pathway. In conclusion, the role of CYP2C9*2 and CYP2C9*3 in attenuation of 4-ene-VPA formation cannot be confirmed.     

VKORC1-3673G>A、CYP2C9*3、CYP4F2 rs2108622和CYP2C19*2基因多态性对中国汉族房颤患者华法林维持剂量的影响

目的 探讨VKORC1-3673G>A、CYP2C9^*3、CYP4F2 rs2108622和CYP2C19^*2位点基因多态性对中国汉族房颤患者华法林维持剂量的影响。方法 收集107例服用华法林达维持剂量的汉族房颤患者的血样和临床相关资料,应用PCR-RFLP法检测VKORC1-3673G>A、CYP2C9^*3、CYP4F2 rs2108622和CYP2C19^*2基因型,采用独立样本t检验分析基因型与华法林维持剂量的相关性。多元线性回归建立给药模型,探讨基因多态性对华法林维持剂量的影响。结果 VKORC1-3673G>A、CYP2C9^*3、CYP4F2 rs2108622基因多态性和患者年龄、体质量能解释45.2%的华法林维持剂量差异。CYP2C19^*2基因多态性对本研究人群华法林维持剂量无影响。结论 VKORC1-3673G>A、CYP2C9^*3、CYP4F2 rs2108622基因多态性显著影响中国汉族房颤患者的华法林维持剂量。     

NCOA6 differentially regulates the expression of the CYP2C9 and CYP3A4 genes

CYP2Cs and CYP3A4 sub families of enzymes of the Cytochrome P450 super family metabolize clinically prescribed therapeutics. Constitutive and induced expressions of these enzymes are under the control of HNF4α and rifampicin activated PXR. In the present study, we show a mechanism for ligand dependent synergistic cross talk between PXR and HNF4α. Two-hybrid screening identified NCOA6 as a HNF4α interacting protein. NCOA6 was also found to interact with PXR through the first LXXLL motif in GST pull down and mammalian two hybrid assays. NCOA6 enhances the synergistic activation of CYP2C9 and CYP3A4 promoter activity by PXR and HNF4α in the presence of rifampicin. However silencing NCOA6 abrogated the synergistic activation and induction of CYP2C9 by PXR–HNF4α but not of CYP3A4. ChIP analysis revealed that NCOA6 could bridge HNF4α and PXR binding sites of the CYP2C9 promoter. Our results indicate that NCOA6 is responsible for the synergistic activation of CYP2C9 by HNF4α and PXR and NCOA6 differentially regulates CYP2C9 and CYP3A4 gene expression though both the genes are regulated by the same nuclear receptors.     

CYP2C9、VKORC1基因多态性对华法令抗凝治疗维持剂量的影响

目的：研究细胞色素P4502C9基因（CYP2C9）和维生素K环氧化物还原酶复合物1基因（VKORC1）在华法令抗凝治疗患者的多态性分布,并探讨其对抗凝剂量的影响。方法：收集74例服用华法令抗凝治疗病人的外周血,测定其凝血酶原时间国际标准化比值（INR）和CYP2C9、VKORC1基因类型,探讨基因多态性的分布特点,以及华法令维持剂量与基因多态性的关系。结果：CYP2C9基因分布主要为野生型,突变型较少,抗凝治疗的维持剂量野生型组与突变组无明显差别。 VKORC1基因型的分布AA型为主,AG型较少,GG型未见,抗凝治疗的维持剂量AG组明显高于AA组。结论：CYP2C9、VKORC1基因在中国汉族人群中具有遗传多态性, VKORC1基因的多态性在华法令抗凝治疗中具有显著意义。     

Dosage recommendation of phenytoin for patients with epilepsy with different CYP2C9/CYP2C19 polymorphisms

To search for the optimal dosage of phenytoin in patients with epilepsy based on the metabolic activities of CYP2C9 and CYP2C19 polymorphisms, a total of 169 patients receiving phenytoin treatment for more than 1 month were recruited. Phenytoin concentration, serum albumin, liver function tests, and renal function tests were measured. CYP2C9 and CYP2C19 polymorphisms were genotyped by PCR-RFLP analysis, and NONMEM models were built to evaluate factors that would affect phenytoin metabolism. Patients were divided into 5 groups according to genotyping results (G1 to G5). Compared with extensive metabolizers in both CYP2C9 and CYP2C19 (G1), the Vmax (mg/kg/d) was 8.29% and 36.96% lower in CYP2C19 poor metabolizers (G3) and CYP2C9 poor metabolizers (G4), respectively. For the patient who was identified as a poor metabolizer in both CYP2C19 and CYP2C9 (G5), the Vmax was 45.75% lower than that of G1. In respect to Km (mg/L), it was 15.09% higher in G3 and 27.36% higher in G4 compared with that in G1. The Km of G5 was 91.71% higher than that of G1. The results revealed that the CYP2C9 and CYP2C19 polymorphisms have dramatic effects on the population pharmacokinetic parameters of phenytoin, especially for CYP2C9. Based on the Vm and Km values obtained in this study, the recommended dose ranges for G1, G2, G3, G4, and G5 patients would be 5.5-7, 5-7, 5-6, 3-4, and 2-3 mg/kg/d, respectively.     

Genetic polymorphisms of cytochrome P450 enzymes 2C9 and 2C19 in a healthy Iranian population

1. The genetically polymorphic cytochrome P450 enzymes 2C9 (CYP2C9) and 2C19 (CYP2C19) are involved in the metabolism and elimination of a number of widely used drugs. The polymorphisms give rise to substantial interindividual and interethnic variability in drug excretion rates and final serum concentrations. For this reason, therapeutic responses and adverse drug reactions may vary from one person to another. In the present study we determined CYP2C9 and CYP2C19 genotypes in a random Iranian population to compare allele frequencies with previous findings in other ethnic groups. 2. Allelic variants of CYP2C9 (*1/*2/*3) and CYP2C19 (*1/*2/*3) were determined in 200 unrelated healthy Iranian volunteers by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays. 3. Fifteen subjects (7.5%) were homozygous for the CYP2C9*2 allele, whereas 21 individuals (10.5%) were heterozygous for this allele and 164 subjects (82%) had the wild-type allele (CYP2C9*1). No CYP2C9*3 was detected in the population sampled. Six subjects (3%) were homozygous for CYP2C19*2, whereas 44 individuals (22%) were heterozygous for this allele. In the remaining subjects (75%), no CYP2C19*2 was found. In addition, no CYP2C19*3 was detected in the population sampled. 4. Based on our data, the frequency of the CYP2C9*2 allelic variant in Iranians is similar to that in other Caucasian populations; however, the frequency of the CYP2C9*3 allele differed significantly (P < 0.05). Conversely, there was no difference in the frequency of CYP2C19 allelic variants between the present study and other studies evaluating this allele in Caucasian populations (P > 0.05).     

Population estimation of the effects of cytochrome P450 2C9 and 2C19 polymorphisms on phenobarbital clearance in Japanese

A nonlinear mixed-effect modeling (NONMEM) program was used to evaluate the effects of cytochrome P450 (CYP) 2C9 and CYP2C19 polymorphisms on the phenobarbital (PB) population clearance for Japanese epileptics. The pharmacokinetics of the 260 PB concentrations at a steady-state obtained from 79 patients was described with a one-compartment open pharmacokinetic model with first-order elimination. The covariates screened included the total body weight (BW), age, gender, PB daily dose, CYP2C9 and CYP2C19 genotypes, the coadministered antiepileptic drugs (AEDs), and complications. The final model of PB apparent clearance was as follows: CL = 0.23 x (BW/40)0.21 x 0.52CYP2C9*1/*3 x 0.68VPA x 0.85PHT x 0.85SMID x (1 + etaCL) where CL = the clearance of PB; CYP2C9*1/*3 = 1, otherwise 0; VPA = 1 if valproic acid is coadministered, otherwise 0; PHT = 1 if phenytoin is coadministered, otherwise 0; SMID = 1 if complications of severe or profound mental retardation with a significant behavior impairment are presented, otherwise 0; and etaCL = the independent random error distributed normally with the mean zero and variance equal to omegaP2. The total clearance of PB decreased by 48% in patients with CYP2C9*1/*3 genotype in comparison with those with CYP2C9*1/*1 genotype (P < 0.001). An effect of CYP2C19 polymorphisms was not detected. To our knowledge, this is the first report to demonstrate that the CYP2C9 genotype affects the PB metabolism in routine care, but the results should be further verified in other ethnic populations.