MDR1C3435T基因多态性对辛伐他汀稳态血药浓度及降脂疗效的影响

目的：研究高脂血症患者MDR1C3435T基因分布及其基因多态性对辛伐他汀稳态血药浓度及降脂疗效的影响。方法：115名高脂血症患者均给予每天20 mg的辛伐他汀治疗4周,在给药前及给药4周后取血样,采用PCR-RFLP（聚合酶链反应-限制性片段长度多态性分析）基因检测技术对MDR1C3435T等位基因进行分析,应用全自动生化分析仪和高效液相色谱仪分别测定血脂及辛伐他汀稳态血药浓度。结果：115名高脂血症患者MDR1C3435T基因型分布符合Hardy-Weinberg遗传平衡（P>0.05）,MDR1C3435T等位基因突变率为40.87％。野生纯合子基因（CC）型组、突变杂合子（CT）型组、突变纯合子（TT）型组之间辛伐他汀稳态血药浓度及降脂疗效无统计学差异（P>0.05）。结论：未发现MDR1C3435T基因多态性对辛伐他汀稳态血药浓度及降脂疗效有明显影响。     

MDR1 C3435T基因多态性对环孢素体内代谢影响的荟萃分析

目的 过荟萃分析进一步观察MDR1 3435T 基因多态性对于环孢素体内代谢的影响。方法 过Pubmed搜索C3435T基因多态性对于环孢素体内代谢影响的相关文献，提取AUC0-4，AUC0-12，AUC0-inf,Cmax,CL/F,和C0等药物动力学参数，使用STATA9.1软件进行荟萃分析。结果 共有14篇参考文献，包括1036名受试者符合本次荟萃分析的入选争件，荟萃分析显示在C3435T野生型杂合子（CC）中，AUC0-12低于其他基因型的受试者。在白种人中，C3435T野生型杂合子（CC）携带者的C0低于其他基因型的白种受试者。其他药物动力学参数在C3435T各基因型之间未见显著差异。结论本荟萃分析没有发现MDR1 C3435T基因多态性对于环孢素体内代谢有较大的影响，但是观察指标的选择是观察结果差异的原因之一；MDR1 C3435T表型和基因型的相关性可能存在种族差异．     

肾移植患者MDR1C3435T基因多态性对他克莫司血药浓度/剂量比及疗效的影响

目的研究肾移植术后患者MDR1C3435T基因多态性对他克莫司（FK506）血药浓度／剂量比（C／D）及急性排斥反应和不良反应的影响。方法采用聚合酶链反应（PCR）和限制性内切片段长度多态性（RFLP）的方法检测肾移植患者MDR1C3435T基因型,比较不同基因型患者之间FK506的C／D值以及急性排斥反应、不良反应的差异。结果MDR1C3435T各基因型组间FK506的C／D值及急性排斥反应、不良反应均无显著性差异。结论MDR1C3435T基因多态性与肾移植患者FK506的C／D值及急性排斥反应、不良反应间无显著相关性。     

MDR1C3435T基因多态性与芬太尼术后镇痛效应的关系

目的探索MDR1C3435T基因多态性与芬太尼术后镇痛效应的关系。方法术后随访患者并记录芬太尼镇痛使用量及不良反应发生情况,采用聚合酶链反应一限制性片段长度多态性（eCR-RFLP）技术对129例患者进行基因分型,比较不同基因型间芬太尼镇痛效应的差异。结果129例患者中、CC型51例（39．5％）、CT型57例（44．2％）、111型21例（16．3％）。CT型、TT型患者24h芬太尼镇痛使用量显著低于CC型（P〈0．05）,TT型患者48h芬太尼镇痛使用量显著低于CC型（P〈0．05）,CT型与CC型48h芬太尼镇痛量、不同基因型组间不良反应发生率差异无统计学意义。结论MDR1C3435T与术后不良反应无相关性,但与芬太尼术后镇痛使用量具有相关性,该基因型可能成为疼痛个体化治疗的参考指标。     

MDR1C1236T基因多态性对环孢素药代动力学影响的系统评价

目的 系统评价MDR1C1236T基因多态性与环孢素(免疫抑制剂)药代动力学的相关性.方法 计算机检索相关数据库,收集MDR1C1236T基因多态性与环孢素药代动力学的相关性研究.用Revman 5.0软件对符合纳入标准的研究进行荟萃分析.结果 共纳入7篇回顾性研究(n=605).分析显示,CC基因型患者给药后2 h,剂量调整浓度明显低于其他基因型;但仅与TT基因型组有统计学差异(P＜0.05),剂量调整谷浓度及平均日剂量与其他基因型问均无统计学差异.结论 MDRI C1236T基因多态性对环孢素给药后2 h剂量调整浓度有一定影响.     

国产环孢素新老剂型对重症肌无力患者血药谷浓度的影响

目的:了解环孢素新老剂型对重症肌无力患者血药谷浓度的影响。方法:回顾性分析环孢素剂型更换前后189例重症肌无力患者的病案、用药记录以及血药浓度检测结果。结果:环孢素血药谷浓度随着每日用药剂量的增加稳步升高;微乳剂环孢素血药谷浓度与测定浓度前日最后一次服药剂量相关,油剂环孢素血药谷浓度与测定浓度前一日服药剂量相关;剂型改变(微乳剂与油剂)对患者血药谷浓度影响差别不大;临床上,根据体重计算两种剂型环孢霉素服用剂量意义不大,其中微乳剂相对于油剂更不适用mg·kg-1换算环孢素用量。结论:环孢素微乳剂逐渐代油剂,如何合理有效的进行剂型转换对重症肌无力疾病的治疗有重要意义。     

CYP3A4,CYP3A5和MDR1基因多态性对环孢素处置的影响

环孢素是一个广泛用于器官移植患者的免疫抑制剂,具有治疗指数窄,不同个体间药代动力学差异较大的特点。它主要通过肝脏和小肠的CYP3A4和CYP3A5代谢;同时它又是药物转运体的底物。不同个体间药物代谢酶和转运体活性的差异可能是造成不同器官移植患者环孢素药代动力学差异的主要原因。而遗传因素即编码药物代谢酶和转运体基因序列的差异可能是其产生活性差异的分子机制。因此,从编码药物代谢酶和转运体的基因入手,可能会为器官移植患者提供最优的治疗方案。     

MDR1基因C3435T多态性对替米沙坦血药浓度与药动学的影响

目的：探讨健康志愿者和高血压患者的多药耐药基因26（exon26）C3435T基因多态性对替米沙坦的血药浓度和药动学的影响。方法：采用聚合酶链反应（PCR）和限制性内切片段多态性（RFLP）的方法对19例健康志愿者和66例高血压患者进行MDR1基因分型。使用HPLC-MS法测定健康志愿者单剂量口服40mg替米沙坦48h内血药浓度和高血压患者的稳态血药浓度。比较不同基因型之间替米沙坦在健康志愿者的药物动力学的差异,和高血压患者的稳态血药浓度差异。结果：C3435T发生率在健康人群和高血压患者之间没有明显的差异,C3435T的3个不同基因型健康志愿者的Cmax,tmax,AUC0-48,AUC0-∞,CL差异无统计学意义（P〉0．05）。3个基因型的高血压患者的稳态血药浓度差异无统计学意义（P〉0．05）。结论：MDR1C3435T基因多态性对替米沙坦的血药浓度和药动学无影响。     

MDR1基因C3435T多态性对替米沙坦稳态血药浓度及降压疗效的影响

目的：探讨多药耐药基因MDR1 C3435T（exon 26）位点基因多态性对替米沙坦在原发性高血压患者中的稳态血药浓度及降压疗效的影响。方法：采用聚合酶链反应（PCR）和限制性内切酶片段多态性（RFLP）的方法对连续30 d每天口服40 mg替米沙坦的61名高血压患者的MDR1C3435T位点进行基因分型。使用高效液相色谱-荧光检测法（HPLC-FLD）测定高血压患者的稳态血药浓度,使用水银血压计测量治疗前、后高血压患者的血压值。比较不同基因型间高血压患者的稳态血药浓度及降压疗效的差异。结果：在61例中老年原发性高血压患者中,MDR1 C3435T CC型纯合子的频率为39.34%,TT型纯合子的频率为11.48%,CT型杂合子的频率为49.18%,MDR1C3435T位点等位基因发生率在健康人群和高血压患者间差异无统计学意义。3种基因型高血压患者的稳态血药浓度及降压有效率间差异无统计学意义（P〉0.05）。结论：MDR1 C3435T位点的基因多态性与高血压患者的稳态血药浓度及降压疗效间无相关性。     

环孢素A在重症肌无力患者中的群体药动学模型的建立

目的:建立环孢素A在重症肌无力患者中的群体药动学模型,了解影响环孢素A代谢的显著影响因素。方法:回顾性搜集82例服用环孢素A的重症肌无力患者的91个血药浓度及其相关资料,利用SPSS软件和逐步回归法分两次建立群体药动学模型,运用内部验证法对模型进行验证。结果:最终所得模型为Ln(Cl/F)=-4.418+1.598Ln(HGB)+0.008W,表明患者的体质量(W)及血红蛋白(HGB)含量对环孢素A在重症肌无力患者体内的代谢影响较大,模型对血药浓度的预测值与实测值误差为15.96%。结论:用SPSS软件和逐步回归法建立的群体药动学型有一定的预测能力,可以用于指导临床给药,并且在样本量增大时,模型会逐渐完善,此法简单易行,值得推广。     

Meta-analysis of the influence of MDR1 C3435T polymorphism on digoxin pharmacokinetics and MDR1 gene expression

AIMS: Studies revealing conflicting results of the functional significance of MDR1 exon 26 C3435T SNP on the disposition of digoxin in different ethnic groups led us to perform a meta-analysis on published data investigating the influence of C3435T SNP on the pharmacokinetics of digoxin and the expression of MDR1. METHODS: Meta-analysis was performed on data from published studies investigating the influence of MDR1 C3435T SNP on digoxin pharmacokinetics, as well as MDR1 expression in Caucasian and Japanese populations. The following outcomes were included: exposures to digoxin measured by area under the concentration-time curve and maximum concentration, the mean intestinal MDR1 mRNA expression and P-gp expression in the absence of digoxin administration. RESULTS: The overall results of the meta-analysis in Caucasian and Japanese subjects suggested no major influence of the C3435T SNP on exposure levels of digoxin as determined by AUC(0-4 h) or AUC(0-24 h) although C(max) values for digoxin were lower in wild-type (CC) subjects compared with subjects harbouring TT genotypes. Subgroup analysis by ethnic populations showed the oral availability of digoxin to be lower in wild-type Caucasian populations compared with wild-type Japanese subjects. No causal relationships were detected between the C3435T SNP and MDR1 mRNA or protein expression. CONCLUSIONS: Our meta-analysis of available studies indicates that the synonymous MDR1 C3435T SNP does not affect the pharmacokinetics of digoxin and the expression of MDR1 mRNA. Future studies should focus on the impact of MDR1 haplotypes on the pharmacokinetics of MDR1 substrates rather than the C3435T SNP alone.     

MDR1 C3435T基因多态性与胃溃疡患者治疗相关性分析

目的 分析MDR1 C3435T基因多态性与胃溃疡患者治疗的相关性.方法 回顾性分析2010年10月至2015年10月来我院就诊的胃溃疡患者共80名,其中Hp阳性患者47例,另选取80例健康体检者作为对照组,测定两组入选对象MDR1 C3435T基因多态性,比较不同基因型胃溃疡患者治疗后Hp阳性率和耐药率.结果 观察组(Hp阳性)患者3435TT基因型频率和T等位基因频率均明显高于观察组(Hp阴性)和对照组(P＜0.05);观察组(Hp阴性)患者3435TT基因型频率和T等位基因频率亦均明显高于对照组(P＜0.05).治疗后3435TT基因型患者Hp阳性率和耐药率均明显高于C3435T和CC3435基因型患者(P＜0.05).结论 MDR1 C3435T基因多态性与胃溃疡患者的治疗具有相关性,3435TT基因型患者较难根除Hp,耐药性较强.     

Meta-analysis of the effect of MDR1 C3435T polymorphism on cyclosporine pharmacokinetics

The published data revealed conflicting results of the polymorphism of MDR1 exon 26 SNP C3435T on the pharmacokinetics of cyclosporine; thus, the aim was to conduct a meta-analysis of significant magnitude to investigate the influence of SNP C3435T on the pharmacokinetics of cyclosporine. A literature search was conducted to locate the relevant papers by using the PubMed electronic source from 1997 and onwards. The pharmacokinetic parameters, including AUC(0-4), AUC(0-12), AUC(0-inf), C(max), CL/F and trough concentration (C(0)), were extracted and a meta-analysis was performed by using Stata version 9.1. A total of 14 papers concerning 1036 individuals were included in the meta-analysis. The overall results showed no major influence of SNP C3435T on the pharmacokinetic parameters, including AUC(0-4), AUC(0-inf), CL/F, C(max) and C(0), although AUC(0-12) was lower in subjects with CC genotype. A subanalysis by ethnic population showed that C(0) was lower in Caucasian individuals harbouring CC genotype. In conclusion, our meta-analysis of available studies has thus far failed to demonstrate a definitive correlation between the SNP C3435T in MDR1 gene and alterations in P-glycoprotein function that can result in altered pharmacokinetics of cyclosporine, although it was indicated in this meta-analysis that the carrier of CC genotype of the SNP C3435T of MDR1 had lower cyclosporine exposure presented as AUC(0-12) than those with at least one T allele. There seems to be ethnic differences in the relationship between the SNP C3435T of MDR1 and cyclosporine pharmacokinetics.     

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.     

Human MDR1 polymorphism: G2677T/A and C3435T have no effect on MDR1 transport activities

The two most frequently observed single nucleotide polymorphisms (SNPs) of the human multidrug resistance 1 (MDR1) gene are 2677G/T/A (893Ala/Ser/Thr) and 3435C/T (no amino acid substitution). In this study, six forms of MDR1 cDNAs with the SNPs were expressed in LLC-PK1 cells and their transport activities were determined. Nearly identical amounts of the recombinant MDR1 proteins were expressed in the established cell lines using the Flp recombinase, which integrates a gene of interest at a specific genomic location. Four structurally diverse compounds: verapamil, digoxin, vinblastine and cyclosporin A, were examined for transcellular transport activities and intracellular accumulation. No significant differences were observed between cells expressing five polymorphic types of the MDR1 cDNAs (2677G/3435T, 2677A/3435C, 2677A/3435T, 2677T/3435C, 2677T/3435T) and cells expressing the wild-type (2677G/3435C). These results suggested that the two frequently observed MDR1 SNPs had no effect on the transport activities of MDR1 proteins expressed in LLC-PK1 cells in vitro, and other genetic or environmental factors might control the expression of MDR1 and the in vivo activity of MDR1.