ABCB1、CYP2B6基因多态性对丙泊酚血药浓度的影响

摘要：目的:探讨药物转运体ABCB1 C3435T与药物代谢酶CYP2B6 G516T基因多态性对丙泊酚血药浓度的影响,为丙泊酚临床个体化给药提供实验室数据。方法:采用荧光染色原位杂交法（FISH）,进行ABCB1 C3435T和CYP2B6 G516T基因多态性检测,用高效液相-荧光法检测血药浓度。根据不同基因型患者使用丙泊酚麻醉后30,60 min给药总量,比较基因多态性与丙泊酚标准化血药浓度的关系。结果:丙泊酚持续给药30 min时,ABCB1 C3435T三种基因型患者给药总量和标准血药浓度比较,差异无统计学意义（P>0.05）;丙泊酚持续给药60 min时,ABCB1不同基因型患者给药总量有明显差异（P<0.05）,ABCB1 C3435T野生纯合子CC基因型患者给药总量高于变异型（CT/TT）患者。给药60 min时,4组患者给药总量差异有统计学意义（P<0.05）。不同CYP2B6 G516T基因型患者在丙泊酚持续给药30 min和60 min时,给药总量和标准血药浓度无相关性。结论:ABCB1 C3435T基因多态性对丙泊酚血药浓度有影响,野生型患者为达到相同的血药浓度需要提高给药剂量。     

卡马西平血药浓度监测及联合用药

目的分析卡马西平治疗癫痫血药浓度与剂量关系.方法用荧光偏振免疫法(FPI A)对不同年龄的2 00例癫痫患者进行卡马西平血药浓度监测,并结合临床分析比较.结果卡马西平稳态血药浓度与给药剂量、给药时间密切相关.结论卡马西平血药浓度监测有着重要意义.     

ABCB1基因多态性与丙戊酸钠治疗癫痫疗效的相关性研究

目的探究ABCB1基因多态性与丙戊酸钠治疗癫痫疗效的相关性。方法选取我院2016年8月～2017年8月收治的140例癫痫患者进行对比调查,依据患者的治疗效果分组,对ABCB1基因多态性与丙戊酸钠治疗癫痫疗效做相关性分析。结果两组患者基因型与等位基因做遗传平衡检验,3个单核苷酸多态性均符合Hardy-Weinberg比例(P> 0.05);不同分型组患者丙戌酸钠体内浓度均未见明显差异;ABCB1基因多态性中不同基因型分布频率分布情况对治疗效果具有影响作用,其中C1236T中集中分布与TT与CC整体治疗效果更佳,C3435T各分型并不会影响到治疗效果,G2677T/A中集中分布在GG与GT治疗效果更为理想。结论研究结果证实ABCB1基因多态性对丙戊酸钠的血药浓度并不存在显著影响,但对于丙戊酸钠治疗癫痫的效果具有一定影响作用,其中C1236T与G2677T/A中基因型分布影响作用最为明显。     

ABCB1基因多态性对肾移植受者环孢素血浓度的影响

目的:研究肾移植术后患者ABCB1基因多态性对环孢素（CsA）血浓度的影响。方法:采用PCR-RFLP（聚合酶链反应-限制性片段长度多态性）方法对339名服用CsA的肾移植患者进行ABCB1基因1236C>T、2677G>T/A和3435C>T多态性检测,荧光偏振免疫法检测肾移植患者CsA血浓度。结果:在339名肾移植患者中,ABCB1基因1236C>T、2677G>T/A和3435C>T突变等位基因频率分别为64.25%、51.54%和35.75%。ABCB1 1236C>T基因多态性检测显示,在移植术后1年,CC基因型个体的CsA血谷浓度明显高于CT和TT基因型个体（P<0.05）。2677G>T/A基因多态性检测提示,在移植术后7d,杂合子GA+GT基因型携带者的C₀高于GG和AA+TT+AT基因型携带者（P<0.05）。3435C>T基因多态性检测表明:在移植术后3个月,突变纯合子TT基因型携带者的C₀低于CC和CT基因型携带者（P<0.05）。其余各时间点,上述3种基因多态性对CsA血谷浓度无明显影响（P>0.05）。结论:ABCB1基因1236C>T、2677G>T/A和3435C>T多态性对极少数时间点的CsA浓度有影响,但对绝大多数时间点的环孢素浓度无影响。     

ABCB1基因多态性对多西他赛药动学和药效学影响的研究进展

由于肿瘤的发生是一个复杂的生物学过程,再加上肿瘤患者存在的个体差异,药物转运蛋白的基因多态性导致的化疗疗效和不良反应显著差异越来越受到人们的重视。多西他赛作为多种肿瘤的有效治疗药物,其存在的疗效、不良反应差异与基因多态性的关系也日益受到人们的关注,其中研究最多的主要是ABCB1的基因多态性。我们就ABCB1的基因多态性情况,ABCB1基因多态性对多西他赛药动学的影响,ABCB1基因多态性与多西他赛疗效、不良反应的相关性几个方面进行综述,以期为临床更合理地运用多西他赛,发挥更有效地抗肿瘤作用并减少不良反应提供参考。     

卡马西平血药浓度变化对癫痫患儿临床疗效的影响

目的:评价卡马西平血药浓度变化对癫痫患儿临床疗效的影响,为癫痫患儿的临床治疗提供参考。方法:选取2012年4月—2015年4月收治的癫痫患儿210例作为研究对象,所有患儿均给予卡马西平治疗,治疗后检测患儿卡马西平血药浓度,分析卡马西平血药浓度变化对癫痫患儿临床疗效影响的相关性。结果:所有患儿经卡马西平治疗后的总有效率并不随血药浓度的升高而增加其疗效,但不良反应的发生率是随其血药浓度的上升而上升,其中卡马西平血药浓度处于4.0~8.0μg/m L范围内,治疗癫痫患者的总有效率为最高(67.21%),且不良发生率较低(11.47%)。结论:提高卡马西平血药浓度并不增加其治疗效果,相反易增加不良反应的发生率,因此监测卡马西平血药浓度控制在治疗窗范围内,可获得最理想的疗效和最低的不良反应。     

儿童卡马西平血药浓度与临床评价

目的：探讨癫痫患儿卡马西平血药浓度与服药剂量、年龄、疗效的相关性。方法：采用荧光偏振免疫分析法测定儿童卡马西平血药浓度1547例/次,将病人的药历等详细资料逐一录入数据库,利用SPSS10．0软件辅助分析。结果：不同年龄儿童卡马西平血药浓度与剂量和疗效之间存在相关,体内的代谢过程有一定的个体差异。结论：治疗药物监测有助于个体化给药、鉴别诊断和了解病人的依从性,以便更好地发挥抗癫痫药的作用,卡马西平抗癫治疗的血药浓度不必过分强调有效浓度低限。     

CYP3A5、ABCB1基因多态性对中国肾移植患者服用他克莫司剂量和血药浓度的影响

目的：研究肾移植患者CYP3A5、ABCB1基因多态性对肾移植术后患者他克莫司（TAC）血药浓度及给药剂量的影响。方法：采集83例中国肾移植患者术后3个月内TAC的常规监测的谷浓度（C0）。测定受试者CYP3A5*3（rs776746）、ABCB1 1236C＞ T（rs1128503）、2677G＞ T/A（rs2032582）、3435C＞ T（rs1045642）位点的基因型,分析基因多态性对TAC的C0、剂量的影响。结果：患者CYP3A5、ABCB1基因型频率均符合Hardy-Weinberg平衡（P ＞ 0.05）。在移植后3个月期间,CYP3A5*3/*3型患者相较于携带*1等位基因患者,具有更高的C0和更低的剂量（P ＜ 0.05）。ABCB1 2677GG基因型的C0显著低于GT、GA、AA、TT、AT型（P ＜ 0.05）;3435CT型的C0显著高于CC、TT型（P ＜ 0.05）。根据ABCB1的单倍型进行分组,并与CYP3A5进行了联合分析,结果发现,发现CYP3A5*1/*1与*1/*3组与*3/*3组中,不同ABCB1单倍型对TAC血药浓度影响的差异无统计学意义。术后随时间延长,CYP3A5*3/*3型患者的TAC剂量逐步降低,而携带*1基因患者的剂量则呈增加趋势。结论：CYP3A5比ABCB1基因多态性对肾移植受者TAC血药浓度的影响更显著,若达到相同的血药浓度,CYP3A5*3/*3型患者每日所服用的剂量更低。根据CYP3A5基因型制定给药方案,有助于尽早达到浓度标准,达到精准治疗的目标。     

189例癫痫患儿卡马西平血药浓度监测结果分析

目的:评价卡马西平的临床合理应用情况。方法:回顾性分析我院189例癫痫患儿应用卡马西平治疗后的血药浓度监测结果。结果:卡马西平血药浓度<4 mg·L~(-1)者32例,其中20例有效(占62.5%);>12 mg·L~(-1)者2例,2例均有效(达100%);4～12 mg·L~(-1)者155例,其中114例有效(占73.5%)。卡马西平单用治疗组与联合治疗组进行有效率比较,P值均>0.05,尚不能认为卡马西平单用组与联合治疗组的总体有效率有差别。结论:卡马西平血药浓度个体差异很大,应通过对其进行监测,并结合临床疗效制定个体化给药方案。     

卡马西平血药浓度监测及联合用药

目的 分析卡马西平治疗癫痫血药浓度与剂量关系。方法 用荧光偏振免疫法(FPIA)对不同年龄的200例癫痫患者进行卡马西平血药浓度监测,并结合临床分析比较。结果 卡马西平稳态血药浓度与给药剂量、给药时间密切相关。结论 卡马西平血药浓度监测有着重要意义。     

Influence of ABCB1 gene polymorphisms on the pharmacokinetics of verapamil among healthy Chinese Han ethnic subjects

AIMS

To assess the association between polymorphisms of the ABCB1 gene and the pharmacokinetics of verapamil among healthy Chinese Han ethnic subjects.

METHODS

Based on polymorphisms of the ABCB1 gene at positions 2677 and 3435, 24 healthy male participants were divided into three groups: 2677GG/3435CC (n = 6), 2677GT/3435CT (n = 12) and 2677TT/3435TT (n = 6). Each subject had received a single oral dose of verapamil (80 mg) under fasting conditions. Multiple blood samples were collected over 24 h, and plasma concentrations of verapamil were determined by HPLC. Pharmacokinetic characteristics were compared between the different genotypic groups.

RESULTS

The pharmacokinetics parameters of verapamil differed significantly among the three genotypic groups. AUC(last) was significantly lower among individuals with the 2677TT/3435TT (159.5 ± 79.0 ng ml⁻¹ h) and 2677GT/3435CT (189.3 ± 73.1 ng ml⁻¹ h) genotypes than those with the 2677GG/3435CC genotype (303.1 ± 83.7 ng ml⁻¹ h) (P= 0.004 and P= 0.008, respectively). However, the CL/F value was higher among subjects with the 2677TT/3435TT (523.0 ± 173.7 l h⁻¹) genotype than those with the 2677GT/3435CT (452.2 ± 188.6 l h⁻¹) or 2677GG/3435CC (265.4 ± 72.8 l h⁻¹) genotypes. A significant difference was also found between the latter two groups (P= 0.034). In addition, the C_max tended to be higher among subjects with the 2677GG/3435CC genotype than those with the 2677GT/3435CT or 2677TT/3435TT genotypes (42.2 ± 3.9 vs 32.2 ± 16.2 vs 38.1 ± 13.7 ng ml⁻¹).

CONCLUSIONS

Our study showed for the first time that verapamil pharmacokinetics may be influenced by particular genetic polymorphisms of the ABCB1 gene among healthy Chinese Han ethnic subjects. An individualized dosage regimen design incorporating such information may improve the efficacy of the drug whilst reducing adverse reactions.     

Effects of long-term carbamazepine treatment on water metabolism and plasma vasopressin concentration

Summary Plasma osmolality, sodium and vasopressin were measured in 7 patients before and during long-term treatment with carbamezepine, under resting conditions, and following an oral water load of 20 ml/kg body weight. During carbamazepine treatment, the ability to excrete the oral water load was decreased, the urine/plasma osmolality ratio was higher, and the free water clearance was lower. In two patients, the ability to excrete the oral water load was severely impaired, and the free water clearance remained negative following water loading. Plasma osmolality and sodium concentration were significantly lower during carbamazepine administration, but despite this the plasma vasopressin concentration remained unchanged or was even slightly increased. Four patients showed inappropriately high vasopressin concentrations in relation to the corresponding plasma osmolality when taking carbamazepine. The findings suggest a decrease in plasma osmolality during carbamazepine treatment, which might account for the inappropriate secretion of vasopressin. The latter might cause clinical symptoms of water intoxication, as has previously been reported in a few patients on carbamazepine therapy.     

ABCB1 polymorphisms may have a minor effect on ciclosporin blood concentrations in myasthenia gravis patients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Numerous studies have shown that MDR1 polymorphisms in the form of single nucleotide poymorphisms or haplptype affect ciclosporin pharmacokinetics or blood concentrations in organ transplantation patients, but some results conflict with others.

WHAT THIS STUDY ADDS

• We had thought that the diease condition might conceal the minor effect of MDR1 polymorphisms.
• We chose myasthenia gravis patients as a population in which disease conditions were less severe.
• We also used different pharmacokinetics indices, such as dose-adjusted trough blood concentrations, dose-adjusted peak blood concentrations and trough blood concentrations under the same ciclosporin regimen.

AIMS

Ciclosporin (CsA), which is widely used in autoimmune disease and transplantation, has a narrow therapeutic index. It also shows considerable interindividual variability in its pharmacokinetics, which may be attributable to polymorphisms of the multidrug efflux pump P-glycoprotein, encoded by MDR-1. The aim was to determine the role of genetic polymorphisms in MDR-1 with respect to interindividual variability of CsA blood concentrations in myasthenia gravis (MG) patients.

METHODS

MG patients (n = 129) receiving CsA were genotyped for MDR-1 1236C→T (exon 12), 2677G→T (exon 21) and 3435C→T (exon 26). Trough blood and peak blood concentrations were determined to see if there was correlation with the corresponding genotype.

RESULTS

We observed a trend for CsA blood concentrations, especially peak blood concentrations, to be higher with the wild-type allele compared with minor alleles in genotype and haplotype. Furthermore, under the same CsA regimen, it was found that the trough concentrations of variant genotype (ABCB1 1236TT or ABCB1 2677TT) were significant greater than those of wild-type (ABCB1 1236CC or ABCB1 2677GG, respectively) (P = 0.0222 and 0.0081). The trough concentrations of wild-type haplotype pair group were significantly lower those that of the mutant type pair group (TT-TT-TT) (P = 0.007).

CONCLUSIONS

ABCB1 polymorphisms in both genotype and haplotype may have a minor effect on the CsA blood concentrations.     

单步萃取-HPLC法测定人血清中卡马西平浓度

目的:建立单步萃取-HPLC法测定人血清中卡马西平浓度的方法。方法:采用Nova-Pak C18柱(3.9mm×150mm,5μm)色谱柱,流动相为甲醇-2mmol.L-1磷酸二氢钠溶液(pH3.5)(50∶50),流速为0.9mL.min-1,检测波长为285nm,柱温为30℃。结果:卡马西平在1.2~32mg.L-1范围内线性关系良好,回归方程:A=5 348.61C-1 891.2,r=0.998 1。方法回收率为99.38%,日内、日间RSD为0.46%~2.02%,最低检测质量浓度为0.3mg.L-1。结论:本法灵敏、准确、快速、专属性强。     

Single nucleotide polymorphisms of ABCB1 (MDR1) gene and distinct haplotype profile in a West Black African population

Objective The ABCB1 (MDR1) multidrug transporter plays a key role in determining drug bioavailability. Differences in drug response exist among different ethnic groups. However, until now, no haplotype data are available in a Black African population.Methods Exons 2, 7, 10, 11, 12, 14, 17, 21, 26, and the surrounding intronic regions were sequenced using genomic DNA from 111 Beninese subjects to examine 19 intragenic single nucleotide polymorphisms (SNPs). Linkage disequilibrium analysis and haplotypes were generated using the expectation–maximization algorithm.Results We identified 12 SNPs, 3 of which were novel: IVS9-57delA, IVS9-8T>A, 1662G>C (exon 14). The most common SNP was IVS14+38A>G. At the MRD1 locus, 53 haplotypes were inferred from the SNP data sets. The 4 SNPs, IVS6+139C>T, IVS9-44A>G, 1236C>T, and 3435C>T, showed strong linkage disequilibrium with each other, confirming the block concept. Moreover, our findings suggest that ABCB1 exonic SNPs are less frequently observed in our population than in African-Americans.Conclusion Our data are compatible with a close evolutionary relationship in Black Africans from Benin.     

卡马西平血药浓度监测与个体化给药

目的：测定卡马西平血药浓度。方法：使用荧光免疫法进行测定。结果：１３０例卡马西平血药浓度测定结果及监测用药的个别典型病例。结论：卡马西平的血药浓度监测在癫痫治疗中具有重要的临床指导意义     

ABCB1（1199G/A）基因多态性对甲磺酸伊马替尼转运的分子机制

摘 要 目的：探讨P 糖蛋白（P-gp）活性和所介导的甲磺酸伊马替尼胞内累积量及药物跨膜渗透性的影响。 方法: 将构建的ABCB1 1199G/wt和1199A/mut重组质粒分别转染HEK293细胞,利用RT-PCR法考察细胞中P-gp的mRNA表达水平。CCK-8法检测药物对细胞的毒性,高效液相色谱法（HPLC）检测细胞中药物浓度和胞内累积量,跨膜电阻实验考察药物跨膜渗透率,评价P-gp活性对药物转运的作用。结果: 细胞毒性实验表明,转染细胞内的药物浓度均低于对照组,证明P-gp具有介导药物转出胞外的作用。HPLC和跨膜电阻实验表明,与野生型ABCB1(1199G)细胞相比,突变型ABCB1(1199A)细胞抗甲磺酸伊马替尼的作用更强,P-gp对介导甲磺酸伊马替尼外排转运的作用较强且药物的跨膜渗透性也相应较强。结论:实验表明ABCB1（1199G/A）位点突变导致其编码蛋白P-gp活性改变,该位点多态性会导致甲磺酸伊马替尼清除率增加,抑制了药物在靶细胞中有效药物浓度,因此临床上应对ABCB1基因进行分型,指导甲磺酸伊马替尼的个体化用药。     

Relationship between the C3435T and G2677T(A) polymorphisms in the ABCB1 gene and P-glycoprotein expression in human liver

AIMS: The aim of the study was to determine whether a correlation exists between MDR1 (ABCB1) gene polymorphisms at positions 3435 (C3435T) and 2677 (G2677T(A)) and the expression of human hepatic P-glycoprotein (P-gp). METHODS: P-gp protein expression in 26 human livers was assessed by Western blotting and ABCB1 mRNA expression was determined by real time RT-PCR. The C3435T and G2677T(A) polymorphisms were identified by RFLP and direct sequence analysis, respectively. RESULTS: The C and G allele frequencies for the C3435T and G2677T(A) polymorphisms were 0.48 and 0.79, respectively, and the genotypes were in Hardy-Weinberg equilibrium. There was a 200- and 20-fold variation in the expression of ABCB1 mRNA and Pgp protein expression, respectively. There were no differences in mRNA and protein expression identified amongst the different genotypes attributable to the C3435T and G2677T(A) polymorphisms in the ABCB1 gene. Exposure to a PXR ligand prior to death did not influence mRNA or protein expression. CONCLUSIONS: There is substantial variability in the expression of Pgp in human liver, but this is not due to the presence of C3435T and G2677T(A) polymorphisms in the ABCB1 gene, although our study is limited by a small sample size.     

Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCG2: therapeutic implications

Pharmacogenomics, the study of the influence of genetic factors on drug action, is increasingly important for predicting pharmacokinetics profiles and/or adverse reactions to drugs. Drug transporters, as well as drug metabolism play pivotal roles in determining the pharmacokinetic profiles of drugs and their overall pharmacological effects. There is an increasing number of reports addressing genetic polymorphisms of drug transporters. However, information regarding the functional impact of genetic polymorphisms in drug transporter genes is still limited. Detailed functional analysis in vitro may provide clear insight into the biochemical and therapeutic significance of genetic polymorphisms. This review addresses functional aspects of the genetic polymorphisms of human ATP-binding cassette transporters, ABCB1 and ABCG2, which are critically involved in the pharmacokinetics of drugs.     

ABCB1基因多态性与五酯胶囊对他克莫司增效作用的相关性研究

摘 要 目的：研究五酯胶囊对他克莫司增效作用与 ABCB1基因多态性的相关性研究。方法: 通过聚合酶链反应 限制性片段长度多态性(PCR RFLP)方法测定ABCB1 1236C>T(rs1128503)、ABCB1 2677G>T/A(rs2032582)和ABCB1 3435C>T(rs1045642)基因型,使用化学发光微粒子免疫分析技术(CMIA)检测他克莫司C0。采用协方差分析考察不同组别患者他克莫司C0/D的差异。结果: 无论是单独使用他克莫司,还是他克莫司与五酯胶囊合用,ABCB1 1236C>T、ABCB1 2677G>T/A、ABCB1 3435C>T 不同基因型及单倍型组的他克莫司C0/D均无显著差异（P>0.05）。结论: 五酯胶囊对他克莫司的增效作用与ABCB1 1236C>T、ABCB1 2677G>T/A、ABCB1 3435C>T基因多态性无关。