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。     

基因多态性对氨氯地平药动学、药效学影响的研究进展

目的:了解基因多态性对氨氯地平药动学和药效学的影响。方法:笔者查阅近年来国内外相关文献,就药物基因组学对氨氯地平药动学和药效学的影响进行归纳和总结。结果:细胞色素P_(450)(CYP)3A、转运体多药耐药(MDR)1、L型电压依赖性钙通道C和D亚单位基因(CACNA1C和CACNA1D)、心钠素前体基因(NPPA)和G蛋白B3亚单位D等基因部分位点是影响氨氯地平药动学、药效学的重要因素。结论:基因多态性与氨氯地平药动学、药效学显著相关。     

基因多态性对麦考酚酸及其代谢产物药动学影响的研究进展

目的:综述近年来国内外学者对基因多态性与麦考酚酸(MPA)及其代谢产物药动学关系的研究,为指导临床合理用药提供循证依据。方法:查阅国内外相关文献,进行系统的文献整理和综合分析。结果:各研究间由于研究对象的病理生理差异、种族差异、突变频率不同、合并用药的影响等,研究结果存在差异。其中,可能与MPA及其代谢产物药动学有关的位点有:UGT2B7 C802T、SLCO1B3 T334G、UGT1A9 T-275A/或C-2152T;存在争议的位点有:UGT1A8*2、UGT1A9 I399C/T、UGT1A9 C-440T、ABCC2 C-24T、ABCG2 C421A;可能无关的位点有:CES2、SLCO1B1、SLCO2B1、ABCB1 C3435T。结论:基因多态性可以影响MPA及其代谢产物的药动学,要进一步阐明基因多态性与MPA及其代谢产物药动学的关系,尚需更多高质量、大样本的体内研究。     

CYP450基因多态性对口服降糖药药动学的影响

介绍了近年来细胞色素P450酶系基因多态性对口服降糖药药动学影响的相关研究,重点指出CYP 2C9*3可能显著降低酶活性,降低药物清除率,升高血药浓度,从而可能改变药效,说明了依基因型调整药物剂量的个体化治疗的必要性。     

UGT1A4基因多态性对儿童拉莫三嗪药动学影响的研究进展

UGT1A4是尿苷二磷酸葡萄糖醛酸基转移酶(UGT)重要的一种亚型,参与生物体内Ⅱ相生物转化,代谢大量的外源性和内源性物质,研究发现UGT1A4基因多态性是多种药物体外代谢速率存在差异的重要原因之一。拉莫三嗪作为一种新型的抗癫痫药物,已广泛用于癫痫患儿的治疗,它主要通过UGT1A4进行代谢,故UGT1A4基因多态性可能会对其代谢产生影响。本文就UGT1A4基因多态性对儿童拉莫三嗪药物动学影响的研究现状作一综述。     

CYP2C19基因多态性对艾司唑仑在人体内药动学的影响

目的：研究健康人CYP2C19基因多态性对艾司唑仑药代动力学的影响。方法：39例健康受试者服用艾司唑仑并测定血药浓度。采用聚合酶链反应-限制性片段长度多态性PCR-RFLP方法确定受试者CYP2C19的基因型,分为野生纯合子、杂合子和突变纯合子。采用3P97软件计算药动学参数,SPSS13.0统计学软件比较CYP2C19基因型中药动学参数的差异。结果：采用PCR-RFLP方法对39例健康受试者的CYP2C19进行分型,杂合子有20例,突变纯合子有19例。CYP2C19基因杂合子强代谢型和弱代谢型比较结果,无统计学差异(P>0.05)。结论：CYP2C19的基因多态性对艾司唑仑的药动学没有显著性影响。     

MTHFR和MTR的基因多态性对马来酸依那普利叶酸片药动学影响的研究

目的:考察亚甲基四氢叶酸还原酶(MTHFR)和蛋氨酸合成酶(MTR)的基因多态性对中国健康成年人口服马来酸依那普利叶酸片后依那普利药动学的影响。方法:36名健康志愿者单剂量口服10mg/0.8mg马来酸依那普利叶酸片后,于不同时间点取血,采用液-质联用法测定血药浓度,并进行血样基因型分析及同型半胱氨酸水平测定。结果:MTHFR存在CC、CT和TT3种基因型,其多态性对依那普利的主要药动学参数未见显著影响;而MTR存在AA、AG2种类型,与AA型相比,AG型对依那普利吸收很好,但排泄较慢。结论:MTHFR基因多态性不影响所研究人群的依那普利药动学,而MTR的AA和AG基因型引起依那普利药动学的差异。     

有机阳离子转运体的基因多态性研究进展

人体的肝脏、肾脏和肠道上广泛分布有各种转运蛋白,其中有机阳离子转运体（OCTs）负责转运一些内、外源性的有机阳离子的转运。在此我们主要讨论的是OCTs家族的成员OCT1和OCT2的基因多态性以及其功能意义。同时我们也就OCT对于药物代谢动力学以及药效学的影响进行阐述,以及OCTs在药物相互作用上的意义。     

UGT1A4基因多态性对儿童拉莫三嗪药动学影响的研究进展

UGT1A4是尿苷二磷酸葡萄糖醛酸基转移酶(UGT)重要的一种亚型,参与生物体内Ⅱ相生物转化,代谢大量的外源性和内源性物质,研究发现UGT1A4基因多态性是多种药物体外代谢速率存在差异的重要原因之一。拉莫三嗪作为一种新型的抗癫痫药物,已广泛用于癫痫患儿的治疗,它主要通过UGT1A4进行代谢,故UGT1A4基因多态性可能会对其代谢产生影响。本文就UGT1A4基因多态性对儿童拉莫三嗪药物动学影响的研究现状作一综述。     

质子泵抑制药的药动学研究进展

摘 要质子泵抑制药（PPIs）为 H+/K+ATP酶抑制药,可高效快速抑制胃酸分泌,持续时间长久,是新型抑酸药物。也是目前治疗酸相关疾病如胃食管反流病、消化性溃疡及非甾体类抗炎药引起的相关胃肠病变的首选药物。对基础胃酸、夜间胃酸的分泌,胃泌素和食物刺激后的引起的胃酸分泌均有显著的抑制作用。本文就国内已上市的5种PPIs的药动学特征进行综述。     

CYP2C9基因多态性与磺酰脲类降糖药药代动力学药效学相关性的研究进展

磺酰脲类是目前临床上广泛使用的口服降糖药，在人体内通过具有基因多态性的CYP2C9酶代谢。不同基因型CYP2C9酶代谢活性的差异，是造成患者所需磺酰脲类口服降糖药剂量个体差异大的因素之一。本文综合国内外最新报道，阐述了CYP2C9基因多态性与磺酰脲类口服降糖药药动学、药效学相关性的研究进展，为制定磺酰脲类降糖药的个体化用药方案提供参者。     

基因多态性对药代动力学和药效学的影响

对同一药物不同病人会产生不同的反应,药物代谢和作用上的差异20％-95％是由基因引起的。已识别出1千4百万单核苷酸的多态性,其中有些与药物的代谢和作用改变有关,有些已用来预测药物的临床反应,多基因参与了药物作用。     

Effect of glutathione S‐transferase genetic polymorphisms on busulfan pharmacokinetics and veno‐occlusive disease in hematopoietic stem cell transplantation: A meta‐analysis

This meta‐analysis was conducted to derive an integrated conclusion about the influence of glutathione S‐transferase (GST) genetic polymorphisms on busulfan pharmacokinetic (PK) parameters and veno‐occlusive disease (VOD). Studies which analysed the effect of GST genetic polymorphisms on area under the curve (AUC), clearance (CL) or VOD were searched for and selected. A pooled analysis was conducted using Comprehensive Meta‐Analysis programme. Nineteen studies were included in this meta‐analysis. GSTA1*B and GSTM1 null genotypes significantly decreased CL_IV of busulfan (standardized difference in means (SDM) = ?1.103; P = 0.019 and SDM = ?0.418; P = 0.002, respectively). GSTA1*B significantly increased AUC_IV of busulfan (SDM = 0.832; P = 0.046), whereas GSTM1 did not (SDM = 0.155; P = 0.478). The PK parameters of oral busulfan did not differ according to GST genotype. GSTA1, GSTM1 and GSTP1 were not significantly associated with VOD occurrence. GSTA1 and GSTM1 genotypes affected CL_IV of busulfan, but only GSTA1 affected AUC_IV. There was no significant difference in the PK parameters of oral busulfan (CL_PO and AUC_PO) and VOD when only GST genotypes were considered.     

Mixed effects of OATP1B1, BCRP and NTCP polymorphisms on the population pharmacokinetics of pravastatin in healthy volunteers

1.?Pravastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor used for the treatment of hyperlipidaemia. This study aims to investigate the effects of genetic polymorphisms in OATP1B1, BCRP and NTCP on pravastatin population pharmacokinetics in healthy Chinese volunteers using a non-linear mixed-effect modelling (NONMEM) approach. A two-compartment model with a first-order absorption and elimination described plasma pravastatin concentrations well.

2.?Genetic polymorphisms of rs4149056 (OATP1B1) and rs2306283 (OATP1B1) were found to be associated with a significant (p?<?0.01) decrease in the apparent clearance from the central compartment (CL/F), while rs2296651 (NTCP) increased CL/F to a significant degree (p?<?0.01). The combination of these three polymorphisms reduced the inter-individual variability of CL/F by 78.8%.

3.?There was minimal effect of rs2231137 (BCRP) and rs2231142 (BCRP) on pravastatin pharmacokinetics (0.01?<?p?<?0.05), whereas rs11045819 (OATP1B1), rs1061018 (BCRP) and rs61745930 (NTCP) genotypes do not appear to be associated with pravastatin pharmacokinetics based on the population model (p?>?0.05).

4.?The current data suggest that the combination of rs4149056, rs2306283 and rs2296651 polymorphisms is an important determinant of pravastatin pharmacokinetics.     

Influence of thiopurine S‐methyltransferase polymorphisms in mercaptopurine pharmacokinetics in healthy volunteers

Mercaptopurine is a drug commonly used in the treatment of different types of cancer, especially acute lymphoblastic leukaemia, and autoimmune diseases such as ulcerative colitis or Crohn's disease and in patients receiving organ transplants. It is metabolized by three cytosolic enzymes. One of them, thiopurine S‐methyltransferase (TPMT), is responsible for catalysing the methylation reaction of mercaptopurine to 6‐methylmercaptopurine, thus inactivating the drug. Individuals with TPMT loss‐of‐function alleles (*2, *3A, *3B or *3C) can be extremely sensitive to the effect of mercaptopurine, since it can be accumulated, therefore producing haematological toxicity. The objective of this study was to evaluate the role of TPMT polymorphisms on the pharmacokinetics of mercaptopurine. For that purpose, we used collected pharmacokinetic data from 48 healthy volunteers (all males) who received a single oral dose of mercaptopurine 50 mg in two bioequivalence studies. The volunteers were subsequently genotyped for TPMT *2, *3A, *3B and *3C alleles by real‐time PCR. There were four carriers (8.3%) of TPMT*2 and TPMT*3A alleles. Mercaptopurine elimination was affected by TPMT loss‐of‐function polymorphisms, since heterozygous subjects show 18% higher half‐life compared to wild‐type individuals. This fact is consistent with the expected since the presence of loss‐of‐function alleles decreases TPMT enzymatic activity and, thus, affects mercaptopurine elimination. Moreover, mercaptopurine pharmacokinetic parameters were different among races, since Latins showed higher plasma concentrations and lower clearance compared to Caucasians. This fact might be due to a different distribution of polymorphisms in genes, other than TPMT, that also influence the pharmacokinetics of mercaptopurine.     

Effects of quercetin on pharmacokinetics of cefprozil in Chinese-Han male volunteers

1.The primary objective of this study was to evaluate the effects of quercetin on the pharmacokinetics of cefprozil. The secondary objective was to evaluate the safety of the combined use of cefprozil and quercetin.

2.An open-label, two-period, crossover phase I trial among 24 Han Chinese male subjects was conducted. Participants were given 500?mg of quercetin orally once daily for 15 d followed by single dose of cefprozil (500?mg) on day 15. Serum concentrations of cefprozil were then measured in all participants on day 15. A 15-d washout period was then assigned after which a 500?mg dose of cefprozil was administered and measured in the serum on day 36.

3.All subjects completed the trial, and no serious adverse events were reported. We measured mean serum concentrations of cefprozil in the presence and absence of quercetin in all participants. The maximum serum concentration of cefprozil in the presence of quercetin was 8.18 ug/ml (95% CI: 7.55–8.81) versus a maximum cefprozil concentration of 8.35 ug/ml (95% CI: 7.51–9.19) in the absence of quercetin. We conclude that the concurrent use of quercetin has no substantial effect on serum concentrations of orally administered cefprozil.

4.Co-administration of quercetin showed no statistically significant effects on the pharmacokinetics of cefprozil in healthy Chinese subjects.     

UGT基因多态性对米格列奈在中国人体内药代动力学个体差异的影响

目的:研究尿苷二磷酸葡萄糖醛酸转移酶(uridine-5'-diphosphate glucuronosyl transferase,UGTs)基因多态性对米格列奈在中国人体内药代动力学个体差异的影响,为临床制定合理的用药方案提供依据。方法:健康受试者单次和多次给药米格列奈片,测定其血药浓度并计算药代动力学参数,同时检测分析UGT1A3和UGT2B7基因多态性。按不同基因型分组,组间药代动力学参数的比较应用单因素方差分析和二独立样本t检验,组间多重差异比较采用LSD-t检验。结果:单次给药后米格列奈药代动力学参数个体差异与UGT1A3和UGT2B7基因多态性间相关性经方差分析和独立样本t检验P>0.05,不存在相关性;多次给药后米格列奈的药代动力学参数个体差异与UGT1A3基因多态性间相关性经方差分析,FAUC=11.279,PAUC=0.001,FCL=16.712,PCL=0.001,差异显著,表明UGT1A3代谢米格列奈的酶活性为UGT1A3*2/*4>UGT1A3*1/*3>UGT1A 3*1/*1>UGT1A3*1/*2>UGT1A3*1/*5;多次给药UGT2B7-1的药代动力学参数FAUC=3....     

Association of CYP3A4*18B polymorphisms with the pharmacokinetics of cyclosporine in healthy subjects

The aim of this study is to evaluate the association of the CYP3A4*18B genotype with the cyclosporine metabolism in healthy subjects. We employed PCR–RFLP assays for analysis of the CYP3A4*18B genotype. Each of 26 subjects, comprising 12 CYP3A4*1/*1, 12 CYP3A4*1/*18B and 2 CYP3A4*18B/*18B, was given a single oral dose of cyclosporine (4?mg?kg^?1). The plasma concentrations of cyclosporine were measured for up to 24?h post dose by high-performance liquid chromatography–electrospray mass spectrometry. We found that the mean C_max (95% confidence intervals) of cyclosporine were 2237 (2905, 1859) (*1/*1), 2247 (2916, 1869) (*1/*18B), and 905 (1192, 506) ng?ml^?1 (*18B/*18B) (p?=?0.037) and the mean AUC0-4 were 5026 (6181, 4372) (*1/*1), 4434 (5481, 3841) (*1/*18B) and 2561 (3155, 1736) ng ml-1?h (*18B/*18B) (p?=?0.021). The CL in the *18B/*18B group was significantly higher than in the *1/*1 group. However, T_max exhibited no difference among the three genotypes. *18B/*18B group showed 50% reduction in concentration at 2?h post dose compared with *1/*18B (p?=?0.062) or *1/*1 (p?=?0.047), but no statistical significance was detected between*1/*1 and *1/*18B groups (p?>?0.05). The data suggest that the CYP3A4*18B genotype affects cyclosporine pharmacokinetics probably resulting from a higher enzymatic activity of this mutation in healthy subjects.