多药抗药基因1 C3435T在中国佤族、白族和藏族人群中的基因多态性

目的了解中国佤族、白族和藏族人群中多药抗药基因1(MDR1)C3435T位点突变频率,并与其他种族比较,了解种族差异。方法使用聚合酶链反应-限制性片段长度多态性方法并用直接测序法对中国143名佤族、138名白族和257名藏族健康个体进行MDR1 C3435T基因分型。结果野生CC型在佤族、白族和藏族的频率分别为31.5%,29.7%和25.7%,突变杂合子CT型频率分别为44.7%,50.7%和56.8%,而突变纯合子TT型频率则分别为23.8%,19.6%和17.5%,分布符合Hardy-Weinberg平衡。MDR1 C3435T等位基因T在佤族、白族和藏族的频率分别为46.2%,44.9%和45.9%,与非洲裔美国人的比较有明显差异。佤族和藏族与汉族的比较有差异。结论中国佤族、白族和藏族人群MDR1C3435T位点的突变发生情况有自己的特点,在临床应用相关药物时,进行该位点基因型检测,将有助于指导临床个体化用药。     

111例心衰患者的 MDR1 和CYP3A 基因多态性与地高辛血药浓度的相关性研究

目的：观察中国贵州地区汉族心衰患者中MDR1C3435T、CYP3A4＊18B和CYP3A5＊3等位基因多态性对地高辛血药浓度的影响。方法：收集111名中国贵州地区汉族心衰患者的血样与地高辛治疗药物浓度监测（TDM）数据,通过PCR-RFLP法分析患者的MDR1C3435T、CYP3A4＊18B及CYP3A5＊3基因型,分析每个基因的多态性对地高辛血药浓度的影响。结果：70岁以上患者MDR1各基因型组中,野生纯合子（CC）组、突变杂合子（CT）组、突变纯合子（TT）组的地高辛血药浓度依次增高。CC组和CT组较TT组的地高辛血药浓度差异有统计学意义（P〈0.05）;CYP3A4和CYP3A5各基因型组之间的地高辛血药浓度差异均无统计学意义（P〉0.05）。结论：MDR1C3435T等位基因突变可使地高辛血药浓度提高;而CYP3A4＊18B和CYP3A5＊3等位基因突变对地高辛的血药浓度无明显影响。     

细胞色素P450 3A5和多药耐药基因遗传变异的联合效应对克拉霉素药代动力学的影响

目的 观察CYP3A5*3和MDR1 C3435T遗传变异的联合效应对中国健康受试者克拉霉素(大环内酯类抗生素)药代动力学的影响.方法 45名受试者服用单剂量克拉霉素胶囊250 mg,HPLC-MS法测定血药浓度.PCR-ASA法和PCR-RFLP法分别测定受试者CYP3A53和MDR1 C3435T的基因型,按基因型分组,比较基因多态性对克拉霉素药代动力学的影响.结果 在45名受试者中,CYP3A5*3各基因型分布,不受MDR1 C3435T基因型的影响;而2者的基因突变均不同程度地协同影响克拉霉素药代动力学参数Cmax、AUC0-24和tmax.结论 CYP3A5*3和MDR1 C3435T遗传变异及协同作用是影响克拉霉素药代动力学特性的重要因素.     

中国汉族、维吾尔族、哈萨克族CYP2D6基因型与表型比较

细胞色素P450 2D6(CYP2D6)是最具有基因多态性的药物代谢酶,在不同种族人群中呈遗传多态性并存在明显的种族差异,目前已发现70多个变异位点[1]。基因突变可以引起酶活性及数量的差异[2],     

影响他汀类药物降脂治疗的相关基因的多态性及其与高脂血症的关系

目的观察他汀类药物降脂治疗相关的基因多态性位点CYP3A4*1G、CYP3A 5*3、MDRl C3435T、SLC21A6 A388G、SLC21A6 T521C、CYP7Al A-204C及ABCG8 T400K在河南地区的分布及其与高脂血症的关系。方法采用聚合酶链反应-限制性片断长度多态性(PCR-RFLP)和等位基因特异性-聚合酶链式反应(AS-PCR)技术对400名高脂血症病人和320名正常对照者进行基因分型。结果等位基因SLC21A6 A388G、SLC21A6 T521C、CYP3A4*1G、CYP3A5*3、MDR1 C3435T、CYP7A1 A-204C及ABCG8 400K的分布频率在高脂血症病人中分别为72.1%、16.2%、27.9%、73.7%、39.9%、34.7%和12.8%,在正常对照组中分别为71.5%、16.1%、27.4%、74.5%、39.4%、33.3%和7.4%;ABCG8 400K等位基因携带者患高脂血症的风险显著增加(OR=1.870,CI:1.259-2.777,P=0.002)。结论CYP3A5*3、MDR1 C3435T、SLC21A6 A388G、SLC21A6 T521C和ABCG8 T400K基因多态性分布可能存在地区或种族差异,ABCG8 400K等位基因是高脂血症的高风险因素。     

尿苷二磷酸葡聚糖转移酶1A8*2在云南健康佤族、白族和藏族基因多态性研究

目的:了解云南佤族、白族和藏族人群中尿苷二磷酸葡聚糖转移酶1A8*2的基因多态性,并与其他种族比较,了解种族差异。方法:使用聚合酶链反应-限制性片段长度多态性的方法对云南144名佤族、115名白族和252名藏族健康个体进行尿苷二磷酸葡聚糖转移酶1A8*2基因分型。计算各民族基因型频率,并检验是否符合Hardy-Weinberg平衡。用χ2检验比较佤族、白族和藏族人群以及已报道的其他民族的基因型频率和等位基因频率。结果:云南佤、白、藏三族健康人群尿苷二磷酸葡聚糖转移酶1A8*2基因频率与文献报道的其他种族比较结果表明,佤族健康人群CC、CG、GG基因型频率分别为16.7%、52.8%和30.5%,白族分别为35.7%、50.4%和13.9%,藏族的分别为8.3%、78.2%和13.5%。佤族、白族和藏族尿苷二磷酸葡聚糖转移酶1A8*2 G等位基因频率分别为56.9%、39.1%和52.6%,与非洲裔美国人及德国高加索人比较其突变率明显增高;白族与日本人比较突变率增高,但突变率低于汉族;云南白族尿苷二磷酸葡聚糖转移酶1A8*2 G等位基因频率与佤族和藏族均有统计学差异(P<0.01),但佤族和藏族之间无差异。上述所有基因型分布比例都符合Hardy-Weinberg平衡。结论:云南佤族、白族和藏族尿苷二磷酸葡聚糖转移酶1A8*2的突变发生情况均有自己的特点,在临床应用相关药物时,进行这些位点基因型检测,将有助于指导临床个体化用药。     

Effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine pharmacokinetics after renal transplantation

1. The calcineurin inhibitor cyclosporine is widely used to prevent allograft rejection after solid organ transplantation. It has a narrow therapeutic index and shows considerable interindividual differences in its pharmacokinetics. Interindividual differences in the activity and expression of the metabolising enzymes cytochrome P450 (CYP) 3A4 and 3A5 and the multidrug efflux pump P-glycoprotein (P-gp) contribute considerably to cyclosporine pharmacokinetics. Variability in the activity of CYP3A4, CYP3A5 and P-gp could be considered to result from genetic polymorphisms encoding their genes. 2. The aim of the present study was to evaluate retrospectively the effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine dose adjusted trough blood concentration during the early period after renal transplantation in Chinese patients. 3. One hundred and six renal transplant recipients in China were genotyped by polymerase chain reaction-restriction fragment length polymorphism for CYP3A4*18A, CYP3A5*3 and MDR1 C3435T. Cyclosporine whole blood levels were measured by fluorescence polarization immunoassay. Dose-adjusted trough blood concentrations (C(0)) were determined and compared among the different genotype groups. 4. The frequency of the CYP3A4*18A, CYP3A5*3 and MDR1 C3435T variant alleles were 0.005 (95% confidence interval (CI) 0.048, 0.0049), 0.783 (95% CI 0.781, 0.785) and 0.528 (95% CI 0.526, 0.531), respectively, and these alleles exhibited incomplete linkage disequilibrium. The median cyclosporine dose-adjusted C(0) in CYP3A5*1/*1 genotype subjects (n = 6) was 14.8 ng/mL per mg per kg (range 11.1-26.8 ng/mL per mg per kg), in CYP3A5*1/*3 patients (n = 34) it was 23.7 ng/mL per mg per kg (range 9.0-61.0 ng/mL per mg per kg) and for CYP3A5*3/*3 patients (n = 66) it was 26.4 ng/mL per mg per kg (range 9.8-85.8 ng/mL per mg per kg; P = 0.012, Kruskal-Wallis test). Accordingly, cyclosporine dose-adjusted C0 was larger in CYP3A5 non-expressors than expressors in the first week after renal transplantation. In addition, wild-type homozygotes (n = 21) for MDR1 C3435T had a slight but significantly lower dose-adjusted C0 compared with heterozygotes (n = 58): 17.7 (10.3-60.8) versus 26.4 (9.0-67.3) ng/mL per mg per kg, respectively (P = 0.014, Mann-Whitney U-test). 5. In conclusion, the present study shows that genetic polymorphisms in CYP3A5 may be responsible, in part, for the large interindividual variability of cyclosporine pharmacokinetics during the early phase after renal transplantation in Chinese patients. Patients with the CYP3A5*3 variant genotype require a low dose of cyclosporine to reach target levels compared with those with the CYP3A5*1 allele.     

Differences in CYP3A5*3 genotype distribution and combinations with other polymorphisms between Spaniards and Other Caucasian populations

The goal of this study was to detect genotypic differences between Spaniards and other related populations regarding CYP3A4*1B, CYP3A5*3, and ABCB1 (MDR1) C3435T polymorphisms. DNA from 177 Spanish patients were analyzed for the presence of these mutations using PCR-restriction fragment length polymorphism or direct sequencing. The observed frequencies for CYP3A4*1B, CYP3A5*3, and C3435T alleles were within normal values in Caucasians (0.04, 0.91, and 0.5, respectively). However, 2.8% of the patients were homozygous for the wild-type CYP3A5*1 allele, an extremely uncommon genotype in other Caucasians. In addition, analysis of CYP3A4-3A5 haplotypes revealed the existence of 2 unusual subgroups: patients who were homozygous wild-type for both polymorphisms, and patients showing a CYP3A4*1A/*1B-CYP3A5*3/*3 genotype combination. The incidence of CYP3A5*1/*1 carriers and the occurrence of subjects combining the 2 above-mentioned unusual genotype combinations were more frequent in Spanish-Caucasians compared with American- or European-Caucasians. ABCB1 C3435T genotype frequencies were equally distributed between both single and combined CYP3A4 and 3A5 genotypes. These findings suggest that dose requirements for drugs metabolized by CYP3A and certain allele-disease association studies in white populations could show discrepancies in Spaniards.     

The effect of CYP3A5 and MDR1 polymorphic expression on cyclosporine oral disposition in renal transplant patients

Variability in CYP3A (CYP3A4/5) and P-glycoprotein (human MDR1 gene product) activity underlies interindividual differences in oral cyclosporine (CsA) bioavailability. Racial differences in polymorphic expression of CYP3A5 and MDR1 may explain observed interracial variability in oral bioavailability. Our objective was to evaluate the effect of CYP3A5 and MDR1 polymorphic expression on CsA oral disposition. Steady-state plasma concentration profiles (n = 19) were sampled in renal transplant recipients receiving concentration-adjusted CsA maintenance therapy. CsA plasma concentrations were measured by fluorescence polarization immunoassay. CYP3A5 and MDR1 genotypes were determined by real-time polymerase chain reaction. Noncompartmental pharmacokinetic analysis and nonlinear mixed-effects modeling (NONMEM) were performed to assess the effect of genotype on CsA pharmacokinetics. MDR1 C3435T genotype was identified as the best predictor of CsA systemic exposure. CsA oral clearance was significantly higher in subjects who carried at least one 3435T allele compared to homozygous wild-type individuals (40.0 +/- 2.2 vs. 26.4 +/- 3.1 L/h, p = 0.007). MDR1 C3435T genotype accounted for 43% of the interindividual variability of CsA oral clearance in the study population after accounting for interoccasion variability. The authors were unable to independently assess whether CYP3A5 correlated with any CsA pharmacokinetic parameter since all CYP3A5 nonexpressors were also 3435T allele carriers. MDR1 3435T allele carriers have enhanced oral clearance compared to individuals with the CC genotype. The frequency of the 3435T allele is lower in African Americans compared to Caucasians. Thus, the MDR1 C3435T genotype offers a potential mechanistic basis to explain interracial differences in CsA oral bioavailability. Further studies are needed to explore the relationship between CYP3A5 and MDR1 genotype and phenotype.     

中国汉族和回族药物代谢酶细胞色素P450(CYP)3A4、CYP2C9、CYP2C19及CYP2D6基因多态性分析

目的对中国汉族、回族健康人群细胞色素P450(CYP)3A4、CYP2C9、CYP2C19及CYP2D6进行基因多态性分析,比较汉族和回族健康人群基因表型和基因频率分布。方法多聚酶链反应-限制性片段长度多态性(PCR-RFLP)法,对300名志愿者的几种基因进行分型。结果汉族、回族CYP3A4*5等位基因频率均为0,CYP3A4*18等位基因频率分别为0.18,0.19;汉族、回族CYP2C9*2等位基因频率分别为0.01,0.05;CYP2C9*13等位基因频率均为0;汉族、回族CYP2C19*2等位基因频率分别为0.39,0.50;CYP2C19*3等位基因频率分别为0.05,0.05;汉族、回族CYP2D6*10等位基因频率分别为0.57,0.39。结论汉族、回族健康人群的CYP3A4*18、CYP2C9*2、CYP2C19*2、CYP2C19*3均没有显著性差异;在汉族、回族健康人群中未发现CYP3A4*5和CYP2C9*13突变;汉族、回族CYP2D6*10等位基因频率有显著性差异(P<0.01);回族人群CYP2D6中速代谢型(*10/*10)频率为13.4%,明显低于汉族的33.1%(P<0.01)。     

The effect of CYP2J2, CYP3A4, CYP3A5 and the MDR1 polymorphisms and gender on the urinary excretion of the metabolites of the H-receptor antihistamine ebastine: a pilot study

AIMS: To determine the effect of gender and the genetic polymorphisms of CYP2J2, CYP3A4, CYP3A5 and MDR1 on the urinary excretion of the H(1) antihistamine ebastine in healthy subjects. METHODS: Eighty-nine Caucasians were studied. The presence of polymorphisms in genes known to be involved in ebastine metabolism and transport (CYP2J2*2,*3,*4,*6,*7, CYP3A4*1B, CYP3A5*3, *6 and MDR1(ABCB1)(C3435T)) was assessed by means of PCR-restriction fragment length polymorphism and sequencing methods. Genotype was correlated with the urinary excretion of the main ebastine metabolites (desalkylebastine and carebastine) under basal conditions and after administration of grapefruit juice. RESULTS: Women excreted statistically greater amounts of desalkylebastine in urine (mean +/- SD (95% confidence intervals, 95% CI), 23.0 +/- 19.5 (18.1, 27.9) micromol) than men (12.4 +/- 11.0 (7.9, 16.9)), (mean difference: 10.6 (2.4, 18.7), P < 0.005). The CYP2J2, CYP3A4 and CYP3A5 analysed polymorphisms did not greatly affect ebastine metabolite excretion. The MDR1(C3435T) polymorphism was found to affect both the urinary excretion of the active metabolite carebastine (32.3 +/- 18.3 (23.1, 41.4), 22.8 +/- 14.7 (18.6, 27.0) and 21.5 +/- 15.3 (14.7, 28.3) for CC, CT and TT carriers, respectively; P < 0.05) and the grapefruit juice-induced inhibition of its transport/formation (mean fold-decrease +/- SD (95% CI), 1.5 +/- 0.8 (1.0, 2.0), 1.1 +/- 0.9 (0.7, 1.4) and 0.9 +/- 0.4 (0.6, 1.2) for CC, CT and TT carriers, respectively; P = 0.01). CONCLUSIONS: Gender and the presence of the MDR1(C3435T) polymorphism both influence the excretion of ebastine metabolites in urine.     

CYP3A5和MDR1基因多态性对中国肝移植患者他克莫司药动学的影响

目的探讨细胞色素P450酶3A5（CYP3A5）基因和多药耐药基因（MDR1）C1236T、G2677T／A、C3435T多态性对肝移植患者口服他克莫司（TAC）后体内药动学参数的影响。方法采集28例肝移植患者手术后第1周和第3周血标本,采用LC—MS／MS法检测TAC血药浓度,计算主要药动学参数。采用聚合酶链反应结合基因测序分析28例肝移植患者CYP3A5＊3和MDR1主要基因型。结果携带MDR1 3435T基因型的肝移植患者口服TAC后,药动学参数AUC0→1和ρmax明显高于3435CC型患者,而CYP3A5＊3、MDR1 C1236T和G2677T／A基因多态性对TAC的药动学参数无明显影响。结论携带MDR1 3435T基因型肝移植患者比3435CC型患者需要较高剂量才能达到目标浓度。     

Pharmacokinetics of paclitaxel in ovarian cancer patients and genetic polymorphisms of CYP2C8, CYP3A4, and MDR1

Interindividual differences in the pharmacokinetics of paclitaxel and its metabolites in Japanese ovarian cancer patients were investigated in relation to genetic polymorphisms of the CYP2C8, CYP3A4, and MDR1 genes. The area under the concentration-time curve (AUC) ratios of paclitaxel/6alpha-hydroxypaclitaxel and paclitaxel/3 -p-hydroxypaclitaxel calculated as the metabolic index of CYP2C8 and CYP3A4 showed 13- and 12-fold interindividual variations, respectively. No patient had any CYP2C8 variants, while 2 patients were heterozygotes of CYP3A4*16. For the MDR1 gene, the frequencies of -129C, 1236C, 2677T, 2677A, and 3435T alleles were 2.2%, 8.7%, 56.5%, 4.4%, and 52.2%, respectively. Subjects possessing the 3435T allele had a significantly (P < .05) higher AUC of 3'- p-hydroxypaclitaxel compared to those possessing the 3435C allele. Leukocytopenia was significantly (P < .05) related to the AUC of paclitaxel. Genotyping of the CYP2C8, CYP3A4, and MDR1 genes might not be essential to predict adverse effects of paclitaxel in Japanese patients, although an allelic variant of MDR1 may functionally affect the pharmacokinetics of its metabolite.     

Intra- and Inter-ethnic Differences in the Allele Frequencies of Cytochrome P450 2B6 Gene in Chinese

Abstract This study aimed to investigate the allele frequencies of CYP2B6 gene in 193 Han Chinese and compared with 91 Uygur Chinese. Five single nucleotide polymorphisms of CYP2B6, 64C>T, 516G>T, 777C>A, 785A>G and 1459C>T, were tested using the polymerase chain reaction–restriction fragment length polymorphism method. The allele frequencies for CYP2B6*2, CYP2B6*3, CYP2B6*4, CYP2B6*5, CYP2B6*6, CYP2B6*7 and CYP2B6*9 in Han and Uygur Chinese were 0.034 and 0.027, 0 and 0.011, 0.091 and 0.033, 0.003 and 0.049, 0.184 and 0.214, 0 and 0.022, and 0.018 and 0.044, respectively, with CYP2B6*4, CYP2B6*5, and CYP2B6*7 being significantly different between these two races (P<0.05). CYP2B6*6 was the most prevalent allele among all detected variants in Han and Uygur Chinese. The most frequent genotypes were CYP2B6*1/CYP2B6*1 (50.8%), CYP2B6*1/CYP2B6*6 (24.4%), and CYP2B6*1/CYP2B6*4 (7.3%) in Han subjects, whereas the most frequent genotypes in Uygur subjects were CYP2B6*1/CYP2B6*1 (36.3%), CYP2B6*1/CYP2B6*6 (25.3%), CYP2B6*1/CYP2B6*5 (5.5%) and CYP2B6*6/CYP2B6*6 (5.5%). The frequencies of 64C>T mutation in Han and Uygur Chinese were significantly lower than that in American Caucasian (P<0.05). These results indicate that there were marked ethnic differences in the mutant frequencies of CYP2B6 between Chinese and other ethnic groups. Further studies are warranted to explore the clinical impact of such ethnic differences.     

An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians

The metabolism of the anticonvulsant drug mephenytoin exhibits a genetic polymorphism in humans. This polymorphism exhibits marked racial heterogeneity, with the poor metabolizer PM phenotype representing 13-23% of oriental populations, but only 2-5% of Caucasian populations. Two defective CYP2C19 alleles (CYP2C19*2 and CYP2C19*3) have been described, which account for more than 99% of Oriental poor metabolizer alleles but only approximately 87% of Caucasian poor metabolizer alleles. Therefore, additional defects presumably contribute to the poor metabolizer in Caucasians. Recent studies have found a third mutation CYP2C19*4, which accounts for approximately 3% of Caucasian poor metabolizer alleles. A fourth rare mutation (CYP2C19*5A) (C99,A991,Ile331;C1297T,Arg433-->Trp) resulting in an Arg433 to Trp substitution in the heme-binding region has been reported in a single Chinese poor metaboliser outlier belonging to the Bai ethnic group. The present study identifies a second variant allele CYP2C19*5B (C99-->T; A991-->G, Ile331-->Val; C1297-T, Arg433-->Trp in one of 37 Caucasian poor metabolizers. The frequency of the CYP2C19*5 alleles is low in Chinese (approximately 0.25% in the Bai ethnic group) and Caucasians (< 0.9%). However, these alleles contribute to the poor metabolizer phenotype in both ethnic groups and increases the sensitivity of the genetic tests for identifying defective alleles to approximately 100% in Chinese poor metabolizers and 92% in Caucasian poor metabolizers genotyped in our laboratory. The Arg433 to Trp mutation in the heme-binding region essentially abolishes activity of recombinant CYP2C19*5A toward S-mephenytoin and tolbutamide, which is consistent with the conclusion that CYP2C19*5 represents poor metabolizer alleles.     

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   

Effects of CYP3A5 and MDR1 single nucleotide polymorphisms on drug interactions between tacrolimus and fluconazole in renal allograft recipients

OBJECTIVE: Drug interactions between tacrolimus and azole antifungals are characterized by a large clinical variability. The aim of this study was to examine the influence of the CYP3A4, CYP3A5, and MDR1 single nucleotide polymorphisms on changes in tacrolimus exposure and dosing in renal allograft recipients treated with fluconazole. METHODS: Twenty-nine patients who had received documented fluconazole treatment were identified out of a total of 753 renal recipients on maintenance tacrolimus therapy. These 29 patients were genotyped for CYP3A4*1/*1B, CYP3A5*1/*3, MDR1 C3435T, and G2677T/A, and the influence of the latter polymorphisms on tacrolimus exposure and dose before, during, and after fluconazole administration was examined. RESULTS: Dose-corrected trough blood tacrolimus concentration did not change significantly from baseline (1.26+/-1.23-fold) in heterozygous CYP3A5*1 carriers during exposure to fluconazole, in contrast to homozygous CYP3A5*3 carriers (3.28+/-2.34-fold; P=0.04 between CYP3A5*3/*3 and CYP3A5*3/*1 genotypes). Homozygous CYP3A5*3 carriers experienced a significant decrease of weight-corrected tacrolimus dose requirements during fluconazole administration (54.7+/-23.7% from baseline, P<0.05) in contrast to heterozygous carriers of CYP3A5*1 (25.1+/-29.9%; P=0.07 between CYP3A5*3/*3 and CYP3A5*3/*1 genotypes). These findings were not influenced by fluconazole dose or duration of administration. Significantly more CYP3A5*3/*3 carriers were exposed to tacrolimus dose-uncorrected trough blood tacrolimus concentration value greater than or equal to 15 ng/ml during administration of fluconazole compared with CYP3A5*3/*1 carriers (73.9 vs. 16.7%, P=0.01). CONCLUSION: In renal allograft recipients the CYP3A5*3/*1 genotype is associated with a reduced susceptibility for the inhibitory effects of fluconazole on tacrolimus metabolism, thereby identifying a genetic determinant of the clinical variability of CYP3A-mediated drug interactions.     

Association of MDR1, CYP3A4*18B, and CYP3A5*3 polymorphisms with cyclosporine pharmacokinetics in Chinese renal transplant recipients

Objective  The objective of this study was to retrospectively evaluate the effects of MDR1, CYP3A4*18B, and CYP3A5*3 genetic polymorphisms on cyclosporine A (CsA) pharmacokinetics in Chinese renal transplant patients during the first month after transplantation. Methods  A total of 103 renal transplant recipients receiving CsA were genotyped for MDR1 (C1236T, G2677T/A, and C3435T), CYP3A4*18B, and CYP3A5*3. The predose and 2-h postdose concentrations of CsA (C₀ and C₂, respectively) were determined by fluorescence polarization immunoassay, and their relationships with corresponding genotypes and haplotypes were investigated. Results  Patients with a CYP3A4*1/*1 genotype were found to have a higher dose-adjusted concentration compared with those with CYP3A4*18B/*18B, as follows: for C₂, 19.3% (P = 0.008) during days 8-15, 35.2% (P = 0.008) during days 16–30, and for C₀, 39.7% (P = 0.012) during days 16–30. The dose-adjusted C₀ was higher in patients with MDR1 1236CC compared with those with 1236TT in the first month postoperation. The dose-adjusted C₀ in patients with the CYP3A5*3/*3 genotype was 25.5% and 30.7% higher than those with the wild-type genotype during days 8–15 (P = 0.011) and days 16–30 (P = 0.015), respectively. Haplotype analysis revealed that the dose-adjusted C₀ was higher in the first month following surgery in carriers of haplotype MDR1 CAC than in noncarriers. Polymorphisms of MDR1 and CYP3A5*3 did not affect dose-adjusted C_2. Conclusion  The data suggests that the CYP3A4*18B genotype affects CsA pharmacokinetics during the first month following surgery in Chinese renal transplant recipients. Patients with CYP3A4*18B alleles may require higher doses of CsA to reach the target levels. Large prospective studies may be needed to further explore the impact of MDR1 and CYP3A5*3 polymorphisms on CsA pharmacokinetics in renal transplant recipients.     

CYP3A5*1-carrying graft liver reduces the concentration/oral dose ratio of tacrolimus in recipients of living-donor liver transplantation

OBJECTIVES: Tacrolimus is widely used for immunosuppressive therapy after organ transplantation, but its pharmacokinetics shows such great interindividual variation that control of its blood concentration is difficult. We have previously reported that an intestinal P-glycoprotein (MDR1) contributes to this variation as an absorptive barrier, but the role of hepatic metabolism is not clear. METHODS: In this study, we have evaluated the genotypes of MDR1 and cytochrome P450 (CYP) 3A in donor and recipient, and the influence of polymorphisms on mRNA expression and the tacrolimus concentration/dose (C/D) ratio in recipients of living-donor liver transplantation (LDLT). RESULTS: The expression level of MDR1 and tacrolimus C/D ratio were not affected by either MDR1 C3435T or G2677T/A. The CYP3A4*1B genotype was not detected, but the CYP3A5*3 genotype had an allelic frequency of 76.3%. The mRNA level of CYP3A5 was significantly reduced by the *3/*3 genotype, and the tacrolimus C/D ratio was decreased in recipients engrafted with partial liver carrying CYP3A5*1/*1 genotype. An analysis of the combination of intestinal MDR1 level and liver CYP3A5 genotype revealed that the tacrolimus C/D ratio was lower in the group with higher MDR1 levels regardless of CYP3A5 genotype during postoperative week 1. CONCLUSIONS: These results indicate that in recipients of LDLT, the pharmacokinetics of tacrolimus is influenced by flux via P-glycoprotein in the intestine during the first week; after that, it is mostly the hepatic metabolism that contributes to the excretion of tacrolimus, and carriers of the CYP3A5*1/*1 genotype require a high dose of tacrolimus to achieve the target concentration.     

MDR1基因多态性和单倍体对肾移植术后稳定期患者他克莫司浓度/剂量比值的影响

目的 探讨MDR1 C1236T、G2677T/A和C3435T 基因多态性和单倍体对中国汉族肾移植术后稳定期患者他克莫司浓度/剂量比值的影响,为他克莫司个体化用药提供依据。方法 采用PCR-基因测序法检测104例肾移植术后稳定期患者MDR1 C1236T、G2677T/A和C3435T 的基因多态性,采用均相酶免疫测定方法(EMIT法)测定他克莫司的谷浓度,比较不同基因型患者之间他克莫司血药浓度/(剂量×体质量)(C/D)比值。结果 104例患者中,MDR1 C1236T、G2677T/A和C3435T突变频率分别为56.73%、55.77%和33.17%。MDR1 C3435T、MDR1 TTT单倍体与他克莫司C/D比值具有相关性(P<0.05)。CYP3A5*3*3患者中,MDR1 TTT单倍体与他克莫司C/D比值仍存在显著相关(P<0.05)。MDR1 C1236T、G2677T/A、CGC单倍体与他克莫司C/D比值无显著性差异(P>0.05)。结论 MDR1 C3435T、MDR1 TTT单倍体与中国汉族肾移植术后稳定期患者他克莫司C/D比值具有显著相关性,是影响肾移植患者他克莫司浓度个体化差异的重要因素。