常见药物转运体基因多态性对药动学影响及研究进展

药物转运体在体内药物的吸收（absorption）、分布（distribution）、代谢（metabolism）及排泄（excretion）的过程（ADME）中发挥着关键的作用。转运体在各组织器官的不同分布以及其基因多态性,导致某些药物的吸收、分布、代谢和排泄过程产生明显的个体差异。随着药物基因组学的快速发展,关于转运体基因多态性的研究报道越来越多。本文对近年来人体主要药物转运体基因多态性在药动学和药效学中的影响研究进行综述。     

Effects of calcineurin inhibitors on sirolimus pharmacokinetics during staggered administration in renal transplant recipients

STUDY OBJECTIVE: To compare the effects of different calcineurin inhibitors on sirolimus pharmacokinetics during long-term, staggered administration in kidney transplant recipients. Design. Randomized, open-label, parallel-group trial. SETTING: A medical center and one of its teaching hospitals in Taiwan. PATIENTS: Twenty-two de novo kidney transplant recipients. INTERVENTION: Patients received cyclosporine microemulsion or tacrolimus capsules twice/day in combination with once-daily sirolimus solution and corticosteroids. Sirolimus was administered 6 hours after the morning dose of cyclosporine or tacrolimus. After receiving a 6-mg loading dose of sirolimus, participants received sirolimus 2 mg/day for at least 7 days. Neither the cyclosporine nor the tacrolimus dosage was adjusted for at least 3 days before and during blood sampling for pharmacokinetic profiling. MEASUREMENTS AND MAIN RESULTS: One patient dropped out because of trimethoprim-sulfamethoxazole-related hepatotoxicity. We observed no differences between the two patient groups in terms of their demographic data, renal and liver function, or dosage of sirolimus during the study. During multiple-dose administration, the area under the whole-blood concentration-time curve and the peak and trough concentrations of sirolimus in the cyclosporine group were, respectively, 1.46 (95% confidence interval [CI] 1.21-1.71), 1.42 (95% CI 1.08-1.76), and 1.42 (95% CI 1.09-1.76) times higher than those of the tacrolimus group, even though sirolimus was administered 6 hours after the other agents. CONCLUSION: Sirolimus pharmacokinetics may change significantly when calcineurin inhibitors are switched, even with staggered administration, which may not completely prevent a drug interaction between cyclosporine and sirolimus solution.     

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。     

Pharmacogenetic effect of the UGT polymorphisms on mycophenolate is modified by calcineurin inhibitors

Background  Mycophenolic acid (MPA) is glucuronidated primarily by uridine diphosphate glucuronosyltransferase enzymes (UGT) 1A9 and 1A8. These enzymes are highly polymorphic resulting in low activity and high expression phenotypes. We hypothesized that polymorphisms of UGT1A9 and 1A8 may alter MPA pharmacokinetics in kidney transplantation. Methods  One hundred seventeen kidney (n = 93), pancreas (n = 11), or simultaneous kidney and pancreas (SPK) (n = 13) transplant recipients were studied for the effect of UGT1A9 and UGT1A8 polymorphisms on MPA dose-corrected trough concentrations. Individuals were genotyped for UGT1A8 and UGT1A9 polymorphisms (1A8*2, 1A8*3, 1A9*3, 1A9-275 and 1A9-2152). Linear regression was used to estimate the effect of UGT polymorphisms on the individual’s mean MPA dose-corrected trough concentration with and without stratification by calcineurin inhibitor. A multiple linear regression analysis was performed to assess the dependence between the average MPA dose-corrected trough concentration and age, gender, UGT genotype (1A8*2, 1A8*3, 1A9*3, 1A9-275, 1A9-2152), serum albumin, hemoglobin (Hgb), hematocrit (HCT), liver transaminases (AST, ALT), serum creatinine, and bilirubin. Results  Mycophenolic acid dose-corrected trough concentrations were 60% higher in subjects heterozygous or homozygous for UGT1A8*2 than in those with the wild type (p = 0.02); however, this effect was dependent on concomitant calcineurin inhibitor. When subjects were stratified by calcineurin inhibitor status, the UGT1A8*2 effect was only apparent in the tacrolimus group (p < 0.01). Mycophenolic acid dose-corrected trough concentrations were 70% lower in carriers of the UGT1A9 -275T>A/-2152 C>T polymorphism who received cyclosporine (p < 0.01). There was no effect of the UGT1A9 -275T>A/-2152C>T polymorphism in the tacrolimus group. Conclusions  The effect of UGT1A8 and UGT1A9 variants on MPA metabolism appears to be modified by concomitant calcineurin inhibitor therapy. Confirmatory in vivo and in vitro studies are needed.     

Digoxin pharmacokinetics and MDR1 genetic polymorphisms

BACKGROUND: The effect of MDR1 C3435T single nucleotide polymorphism (SNP) in exon 26 on digoxin pharmacokinetics has recently been challenged. OBJECTIVE. To clarify the relationships between MDR1 genetic polymorphisms in exon 26 (C3435T) and 21 (G2677T/A) and digoxin pharmacokinetics. MATERIALS AND METHODS: MDR1 genotypes for C3435T and G2677T/A SNPs were determined in 32 healthy subjects whose single oral dose digoxin pharmacokinetics had been measured over 48 h. RESULTS: A significant relationship was observed between C3435T SNP and digoxin AUCs ( p<0,05). Homozygous TT subjects had 20% higher digoxin plasma concentrations than CT and CC subjects and a trend for higher 48 h digoxin urinary recoveries (TT>CT>CC). Similar results, although not statistically significant, were observed from the MDR1 G2677T/A SNP. CONCLUSIONS: Our results confirm that the MDR1 C3435T single nucleotide polymorphism (SNP) significantly affects digoxin disposition kinetics, with homozygous TT subjects presenting the highest plasma concentrations.     

Effects of calcineurin inhibitors on pharmacokinetics of mycophenolic acid and its glucuronide metabolite during the maintenance period following renal transplantation

Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF) has been introduced into renal transplant immunosuppressant protocols in combination with calcineurin inhibitors (CNIs) and steroids. This study compared the pharmacokinetic profiles of MPA and its major metabolite MPA glucuronide (MPAG) in combination with tacrolimus (TAC) or cyclosporine (CyA) during the maintenance period (>6 months) following renal transplantation. There was no difference between TAC and CyA-treated groups in MPA plasma concentration before drug administration (C(0)). MPA C(0) in TAC and CyA-treated patients did not differ from that in patients who were not treated with a CNI. In patients treated with a CNI, MPAG C(0) was significantly greater in those treated with CyA compared with TAC. The MPAG/MPA ratio in CyA-treated patients was significantly greater than that in the TAC-treated group. We observed that C(0) of MPA was negatively correlated with that of TAC and CyA. Positive correlation between MPA C(0), MPAG C(0) and serum creatinine was stronger in patients treated with CyA compared with TAC. Our study suggests that CyA, but not TAC, inhibits enterohepatic circulation of MPAG as a secondary excretion pathway, and that renal function makes a major contribution to elimination of MPA and MPAG. We indicate that it may be necessary to estimate biliary excretion of MPAG to avoid the risk of intestinal injury in patients receiving combination therapy with TAC during the maintenance period.     

钙调神经磷酸酶抑制剂的研究进展

钙调神经磷酸酶是迄今发现的唯一受Ca2+或钙调素调节的丝氨酸苏氨酸蛋白质磷酸酶,参与多种细胞功能的调节。该酶的抑制剂在移植免疫等方面的研究方兴未艾。此文综述了国外对该酶抑制剂的研究进展。     

CYP3A4基因多态性对健康受试者体内替硝唑药代动力学的影响（英文）

研究中国汉族人群CYP3A4^*18B基因多态性的频率,并探讨CYP3A4^*18B基因多态性对替硝唑药代动力学的影响。本研究共招募100名来自中国汉族的健康志愿者,采用PCR-RFLP方法检测CYP3A4^*18B的基因多态性。选择CYP3A4^*1/^*1(n=10)野生型受试者和CYP3A4^*1/^*18B(n=9)突变杂合型受试者进行替硝唑的药代动力学研究。单剂量口服替硝唑片剂后采集72h内的血样,使用高效液相色谱法测定血浆样本中替硝唑的浓度。发现88名健康志愿者携带CYP3A4^*1/^*1基因型,12人携带CYP3A4^*1/^*18B基因型,未发现携带CYP3A4^*18B/^*18B基因型。CYP3A4^*18B等位基因频率为6%。CYP3A4*1/*1基因型和CYP3A4^*     

Effects of UDP-glucuronosyltransferase polymorphisms on the pharmacokinetics of ezetimibe in healthy subjects

Purpose  

Ezetimibe is the first lipid-lowering drug that inhibits the intestinal uptake of dietary and biliary cholesterol without affecting the absorption of fat-soluble nutrients. Ezetimibe is readily absorbed, and undergoes rapid and almost complete glucuronidation by UGT, particularly UGT1A1, in enterocytes during its first pass. Genetic polymorphisms of UGT1A1 may decrease ezetimibe glucuronidation. Therefore, we tested the effects of the UGT1A1*6 and *28 alleles on the pharmacokinetics of ezetimibe.     

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....     

基因多态性对氟伐他汀药代动力学和药效学特征的影响

氟伐他汀是第一个全化学合成的降胆固醇药物,在临床治疗应用中存在较大的个体疗效差异。肌毒性、肝毒性,横纹肌溶解等是氟伐他汀的潜在不良反应。为了降低不良反应的发生率,研究导致氟伐他汀个体差异大的原因具有重大意义。本文综述了CYP450酶、药物转运体（OATPlBl、OATPlB3、OATP281、ABCG2）多态性对氟伐他汀药代动力学特征的影响和药效基因（CETP、ApoE）的多态性对氟伐他汀药效学特征的影响。以期确保临床用药的安全性和有效性,真正实现临床上的个体化给药。     

Molecular actions of calcineurin inhibitors

The immunosuppressive drugs cyclosporin A and FK-506, also called calcineurin inhibitors, have been useful for treating immune system-mediated diseases and have truly revolutionized allograft transplantation. Both drugs block T-cell proliferation by mechanisms that involve the inhibition of the key signaling phosphatase calcineurin, hence, the name calcineurin inhibitors. The inhibition of calcineurin activation by cyclosporin A and FK-506 blocks T-cell receptor-mediated production of interleukin-2 (IL-2), a growth factor critical for T-cell proliferation. Recent studies, however, suggest that the effects of the drugs are not limited to blocking calcineurin activation and IL-2 production. This review discusses the molecular actions of cyclosporin A and FK-506.     

CYP2C19基因多态性对伏立康唑药代动力学影响的系统评价

目的系统评价CYP2C19基因多态性与伏立康唑药物代谢动力学的关系。方法至2011年2月,计算机检索Cochrane图书馆、PubMed、Embase、Med-line、CNKI等数据库。收集有关CYP2C19基因多态性与伏立康唑药代动力学关系的研究。用RevMan 5.0软件对符合纳入标准的研究进行Meta分析。结果共纳入10篇回顾性研究。其中,英文9篇,中文1篇。Meta分析结果表明,3种基因型对Cmax的影响没有统计学差异;3种基因型对AUC和T1/2的影响十分明显,PM基因型组的AUC和T1/2的值均大于HEM基因型组,且HEM基因型组均显著大于EM基因型组。基因型为EM人群的CL/F,明显大于PM基因型组;基因型为PM的人群Tmax,显著长于EM组;基因型为PM人群的MRT,显著大于EM人群。结论伏立康唑代谢与CYP2C19基因多态性有显著相关性;但可能还受其他多种因素影响。     

MDR1 C1236T、G2677T/A、C3435T的基因多态性对中国汉族肾移植患者环孢素药动学的影响(英文)

目的探讨中国汉族人中肾移植患者的多药耐药基因(MDR1)外显子exon12 C1236T、exon21 G2677T/A、exon26 C3435T的单核苷酸多态性对免疫抑制剂环孢素(CsA)药动学的影响。方法采用聚合酶联反应和限制性内切片段长度多态性(PCR-RFLP)的方法对89例肾移植术后的患者进行MDR1基因分型。单克隆抗体荧光免疫偏振法测定患者术后CsA的谷浓度(c0)及服药后2 h浓度(c2)。比较不同基因型之间CsA浓度剂量比值的差异。结果在89例肾移植患者中,等位基因1236T、2677T、2677A、3435T突变频率分别为66%、43%、18%和37%。肾移植术后1 mo内,G2677T/A基因多态性与CsA的药动学有相关性,2个等位基因都发生突变的患者,其剂量校正c0,在术后1~7 d、8~15 d和16~30 d比野生型分别提高51%(P=0.005)、32%(P=0.002)和63%(P<0.001)。在术后16~30 d,无论携带有1个或2个突变等位基因的患者,剂量校正c2都要比野生型患者高26%(P=0.007)和19%(P=0.041)。C1236T的剂量校正c0在术后8~15...     

细胞色素P450 2C19、3A5和多药耐药基因多态性对兰索拉唑代谢的影响

目的研究细胞色素P4503A5*3、多药耐药基因C3435T和细胞色素P450 2C19*2突变对兰索拉唑(抗胃酸药)药代动力学的影响。方法24名健康志愿者单次口服兰索拉唑30 mg后,用HPLC方法测定血浆中的兰索拉唑浓度,研究在中国汉族健康人中兰索拉唑的体内过程与基因型的相关性。结果细胞色素P4502C19*1/*1与*2/* 2比较,AUC_(0-∞)存在显著性差异(P=0.04),表达CYP2C19*2/*2的受试者体内兰索拉唑的暴露量是*1/*1者的1.75倍;MDR1 3435C与3435TT比较,t_(max)、AUC_(0-2)存在显著性差异(P=0.026,P=0.03),但总暴露量(AUC_(0-∞))2组间没有差异,表明CYP3A5*3各基因型间药代动力学参数不存在显著性差异。结论CYP2C19*2/*2突变使兰索拉唑体内暴露量增大;MDR1 3435TT基因型者兰索拉唑起始吸收速率较大,达峰快;但该基因型对其总吸收量没有影响,CYP3A5*3对兰索拉唑药代动力学没有影响。     

The implications of genetic variation for the pharmacokinetics and pharmacodynamics of aromatase inhibitors

Introduction: Breast cancer is the most common female cancer and remains a serious public health concern worldwide. Third-generation aromatase inhibitors (AIs) are widely used in postmenopausal women with estrogen receptor positive breast cancer. However, there is marked interindividual variability in terms of the efficacy and incidence of adverse events following treatment with AIs. Pharmacogenetics has the potential to predict clinical outcomes based on patients’ genetic information, paving the way towards personalized treatment.

Areas covered: This article reviews pharmacogenetic studies of AIs, including pharmacokinetic and pharmacodynamic aspects, highlighting those studies where the efficacy and adverse events of AIs have been examined using both candidate gene and genome-wide approaches.

Expert opinion: Pharmacogenetics is a promising approach to develop personalized medicine with AIs. However, the application of pharmacogenetics to predict therapeutic efficacy and adverse events in breast cancer patients is still far from implementation in routine clinical practice. Large, comprehensive, multicenter studies that simultaneously evaluate multiple genes and pathways, including rare variants, are warranted in order to produce reliable and informative results. The ultimate aim is to develop clinically-relevant guidelines for breast cancer therapy.     

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。     

Influence of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its metabolites

In-vitro data indicate major effects of the genetically polymorphic cytochrome P450 enzyme 2C9 (CYP2C9) on the pharmacokinetics of celecoxib, a nonsteroidal anti-inflammatory drug acting as selective cyclooxygenase-2 inhibitor. Human studies report decreased clearance in heterozygous carriers of the CYP2C9 variant Ile359Leu (*3), but results appeared controversial and only data on single subjects carrying the homozygous CYP2C9*3/*3 genotype have been published. We measured single-dose kinetics of celecoxib and its main metabolites hydroxy- and carboxy-celecoxib in 21 healthy volunteers who were selected as hetero- (n = 4) and homozygous (n = 3) carriers of CYP2C9 variants Arg144Cys (*2) and Ile359Leu (*3). Blood concentrations of celecoxib and its metabolites hydroxy-celecoxib and carboxy-celecoxib were quantified by high-performance liquid chromatography. A more than two-fold reduced oral clearance in homozygous carriers of CYP2C9*3 was seen for celecoxib compared to carriers of the wild-type genotype CYP2C9*1/*1 and heterozygous carriers of one *3 allele were in-between (P = 0.003 for trend), whereas CYP2C9*2 had no significant influence on celecoxib pharmacokinetics. Decreased concentrations of carboxy- and hydroxy-celecoxib in heterozygous and homozygous carriers of CYP2C9*3 were detected which supported the influence of CYP2C9 polymorphisms on celecoxib pharmacokinetic variability. Approximately 0.5% of Caucasians carrying the genotype CYP2C9*3/*3 will have greatly increased internal exposure to celecoxib. It remains to be shown whether this is associated with greater efficacy or with an increased incidence and severity of adverse events.     

瑞格列奈药代动力学特征及有关基因多态性对其药代和药物相互作用的影响

瑞格列奈是一种具有氨基酸结构的非磺脲类促胰岛素分泌的口服降糖药,降血糖作用快而短,模拟胰岛素生理性分泌,主要用于控制高血糖,同时减少低血糖的发生。本文将对瑞格列奈的药代动力学特征、基因组学研究进展、药物相互作用作一综述。以期为指导瑞格列奈的临床用药打下坚实的理论基础,确保临床用药的安全性和有效性,真正实现临床上的个体化给药。     

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.