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 C1236T和G2677T/A基因多态性对肾移植受者他克莫司血药浓度影响的Meta分析

目的：系统评价多药耐药基因1（MDR1）C1236T和G2677T/A多态性对肾移植受者他克莫司（FK506）血药浓度的影响,为临床个体化应用FK506提供循证参考。方法：计算机检索PubMed、Embase、Cochrane Library、CNKI数据库和万方数据库,检索时限均为建库起至2020年11月。收集MDR1（C1236T,G2677T/A）基因多态性对肾移植受者FK506血药浓度影响的研究,用Rev Man 5.3软件进行Meta分析。结果：共纳入12篇（中文5篇,英文7篇）相关研究,共计1 083例患者。其中,涉及C1236T的研究为9项,涉及G2677T/A的研究为10项。Meta分析结果显示：MDR1 C1236T基因型方面：MDR1 C1236T基因中CC型患者与CT型比较,FK506血药浓度/校正剂量值差异无统计学意义[SMD＝2.18,95% CI （-2.84,7.19）,P=0.40];MDR1 C1236T基因中CC型患者与TT型比较,FK506血药浓度/校正剂量值差异无统计学意义[SMD＝6.02,95% CI （-4.12,16.17）,P=0.24];MDR1 C1236T基因中CT型患者与TT型比较,FK506血药浓度/校正剂量值差异无统计学意义[SMD＝-0.13,95% CI （-7.71,7.44）,P=0.97]。MDR1 G2677T/A基因型方面：MDR1 G2677T/A基因中GG型患者FK506血药浓度/校正剂量值显著低于GA+GT型[SMD＝-6.91,95% CI （-12.39,-1.42）,P=0.01],亚组分析结果显示：术后12月[SMD＝-18.62,95% CI （-23.41,-13.82）,P<0.000 01],MDR1 G2677T/A基因中GG型患者FK506血药浓度/校正剂量值显著低于GA+GT型;MDR1 G2677T/A基因中GG型患者FK506血药浓度/校正剂量值显著低于TT+TA+AA[SMD＝-9.15,95% CI （-16.68,-1.61）,P=0.02],亚组分析结果显示：术后12月[SMD＝-19.81,95% CI （-39.29,-0.32）,P=0.05],MDR1 G2677T/A基因中GG型患者FK506血药浓度/校正剂量值显著低于TT+TA+AA;MDR1 G2677T/A基因中GA+GT型患者FK506血药浓度/校正剂量值与TT+TA+AA型比较,差异无统计学意义[SMD＝-4.56,95% CI （-9.32,0.19）,P=0.06]。结论：MDR1G2677T/A基因多态性与FK506血药浓度/校正剂量值有一定的相关性,且GA+GT或者TT+TA+AA型>GG型,而MDR1 C1236T基因多态性与肾移植受者FK506血药浓度/校正剂量值无相关性。     

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。     

肾移植患者MRP2C3972T基因多态性对吗替麦考酚酯药动学参数、不良反应及急性排斥反应的影响

目的：研究MRP2 C3972T基因突变对肾移植术后患者服用吗替麦考酚酯药动学参数.不良反应及急性排斥反应的影响.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）方法检测肾移植患者MRP2 C3972T基因型,比较不同基因型患者之间吗替麦考酚酯的药动学参数.不良反应及急性排斥反应发生率的差异.结果：肾移植术后第7天.第14天.第30天各基因型患者在C0、C0/D、AUC0-12、AUC0-12/D等值上没有显著性差异,但突变型患者（C/C＋T/T）在术后第7天、第14天、第30天的C0/D、AUC0-12/D均低于野生型（C/C）患者.三组间不良反应及急性排斥反应发生率没有显著差异.结论：MRP2C3972T突变可以在一定程度上降低血浆中麦考酚酸的浓度.     

Minimal effect of MDR1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of indinavir in HIV-infected patients

AIMS: The protease inhibitor indinavir is characterized by an important interindividual pharmacokinetic variability, which results from the actions of the metabolizing enzymes cytochrome P450 (CYP) 3A and the multidrug efflux pump P-glycoprotein (P-gp), encoded by MDR1. Using a population pharmacokinetic approach, we investigated the effect of several MDR1 and CYP3A5 polymorphisms on the pharmacokinetic parameters of indinavir in HIV-infected patients. METHODS: Twenty-eight patients receiving indinavir alone or together with ritonavir were included. Indinavir pharmacokinetics were studied over a 12 h interval. Genetic polymorphisms were assessed by real-time PCR assays and direct sequencing for MDR1 and by PCR-SSCP analysis for CYP3A5. RESULTS: The pharmacokinetics of indinavir were best described by a one-compartment model with first-order absorption. In the final model, the MDR1 C3435T genotype and ritonavir were identified as statistically significant covariates (P 相似文献   

中国汉族肾移植术后稳定期患者MDR1基因多态性与口服环孢素A谷质量浓度的相关性探讨

目的研究中国汉族肾移植术后稳定期(>1 a)患者服用环孢素A(cyclosporine A,CsA)的谷质量浓度与多耐药基因(multidrug resistance gene,MDR1)C3435T多态性的相关性。方法采用聚合酶链反应结合限制性片段长度多态性(PCR-RFLP)分析法检测87例肾移植术后患者MDR1C3435T基因多态性,结合口服环孢素A的谷质量浓度,判断二者是否存在关联。所有血样均为肾移植术后稳定期患者的血样。结果 87例患者中,C/C型36例(41.4%),C/T型42例(48.3%)和T/T型9例(10.3%)。87例患者CsA谷质量浓度的均值为(169.5±71.8)μg.L-1(中位数为157.4μg.L-1;范围为76.6~410.9μg.L-1)。C3435T基因多态性与CsA谷质量浓度无显著性差异(P>0.05)。结论 C3435T基因多态性不是影响中国肾移植稳定期患者口服CsA谷质量浓度的主要因素。     

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。     

MDR1基因多态性对相关药物药动学影响研究进展

药物在体内的处置通常是由转运蛋白参与完成的。其中的P-糖蛋白(P-gp),由多药耐药基因MDR1编码,其作用是加速药物从这些组织的外排。MDR1基因多态性直接影响P-gp的分布和功能,并影响着P-gp底物药物的体内处置。因此对于不同基因型编码的P-gp的生理和生化功能的进一步研究对个体化药物治疗非常重要。本文就目前研究较多的MDR1基因单核苷酸多态性对不同底物的药动学影响进行了综述,为临床个体用药提供一定的参考。     

Influence of carboxylesterase 2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients

1. Mycophenolic acid (MPA), converted from the prodrug mycophenolate mofetil (MMF), is generated by intestinal and hepatic esterases. The role of carboxylesterase (CES) in MMF hydrolysis was examined in vitro using human liver microsomes. V_max and K_m values of MMF hydrolysis in pooled human liver microsomes were 1368?±?44 nmol min^?1 mg^?1 protein and 1030?±?65?μM, respectively.

2. Hydrolytic activity was inhibited by the CES inhibitors phenylmethylsulfonylfluoride, bis-p-nitorophenylphosphate and diisopropylfluorophosphate, with IC₅₀ values of 77.1, 3.59 and 0.0312?μM, respectively.

3. Eighty Japanese renal transplant recipients that received repeated-doses of MMF, tacrolimus and prednisolone, were evaluated for MPA pharmacokinetics 28 days after transplantation to investigate the relationship between MPA pharmacokinetics and CES2 genetic polymorphisms.

4. No significant differences in MPA pharmacokinetics were observed between CES2 A4595G, C8721T or A-1548G genotype groups. CES2 allelic variants also did not appear to affect plasma MPA concentrations between individuals.

5. In conclusion, the study demonstrated that while CES1 and/or CES2 are involved in the hydrolysis of MMF to MPA, CES2 allelic variants appeared to make only a minor contribution to inter-personal differences in MPA pharmacokinetics.

     

多药耐药基因MDR1多态性的研究进展

MDR1所编码的P-糖蛋白是ABC蛋白家族成员之一,它在体内药物的转运和处置中发挥着重要作用。本文就近几年有关MDR1基因多态性对P-糖蛋白在组织中表达的影响、以及MDR1多态性对药物处置、临床疗效以及疾病风险等影响进行综述。     

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.     

Associations of UDP-glucuronosyltransferases polymorphisms with mycophenolate mofetil pharmacokinetics in Chinese renal transplant patients

Aim:

To evaluate the effects of UDP-glucuronosyltransferases (UGTs) polymorphisms on the pharmacokinetics of the immunosuppressant mycophenolate mofetil (MMF) in Chinese renal transplant recipients.

Methods:

A total of 127 renal transplant patients receiving MMF were genotyped for polymorphisms in UGT1A9 −1818T>C, I399C>T, −118T9/10, −440C>T, −331T>C, UGT2B7 IVS1+985A>G, 211G>T, −900A>G, UGT1A8 518C>G and UGT1A7 622T>C. The plasma concentrations of the MMF active moiety mycophenolic acid (MPA) and main metabolite 7-O-MPA-glucuronide (MPAG) were analyzed using HPLC. Univariate and multivariate analyses were used to assess the effects of UGT-related gene polymorphisms on MPA pharmacokinetics.

Results:

The dose-adjusted MPA AUC_{0–12 h} of the patients with the UGT2B7 IVS1+985AG genotype was 48% higher than that of the patients with the IVS1+985AA genotype, which could explain 11.2% of the inter-individual variation in MPA pharmacokinetics. The dose-adjusted MPAG AUC_{0–12 h} of the patients with the UGT1A7 622CC and UGT1A9 −440CT/−331TC genotypes, respectively, was significantly higher than that of the patients with 622T homozygotes and −440C/−331T homozygotes. Furthermore, the genotypes UGT1A9 −1818T>C and UGT1A8 518C>G were associated with a low dose-adjusted MPAG AUC_{0–12 h}.

Conclusion:

The UGT2B7 11+985A>G genotype is associated with the pharmacokinetics of MPA in Chinese renal transplant patients, which demonstrates the usefulness of this SNP for individualizing MMF dosing.     

肾移植受者环孢素血药浓度监测频度及其临床意义

目的:研究肾移植术后患者环抱素(CsA)血药浓度监测频度的临床意义。方法:对24例肾移植术后患者296次CsA血药浓度监测进行回顾性分析,分2组:规律组15例201次规律性监测;非规律组9例95次因各种原因不能定期监测。比较2组CsA血药浓度统计学变异系数(CV)的差异及排斥反应组与非排斥反应组CsA血药浓度CV的差异。结果:规律组CsA血药浓度CV小于非规律组(P<0.05);非排斥组CsA血药浓度CV小于排斥组(P<0.05)。结论:规律性CsA血药浓度比非规律性监测平稳;排斥反应的发生率与CsA血药浓度的CV呈正相关。