霉酚酸酯药代动力学与多重耐药基因1多态性的相关性研究

目的 研究肾移植受者术后早期霉酚酸酯(MMF)的药代动力学与人类多重耐药基因1(MDRI)多态性的相关性.方法 选择初次肾移植的汉族受者28例,肾移植术后2周时,于口服MMF之前及服药后0.5、1、1.5、2、4、6、8、10、12 h共10个时间点分别采集外周血,以高效液相色谱(HPLC)法测定全血霉酚酸酯(MMF)的活性成分霉酚酸(MPA)的浓度,直接观察其峰值浓度(Cmax)和达峰时间(Tmax).应用Winnolin 3.1软件计算MPA 0～12 h药物时间一浓度曲线下面积(AUC)和平均滞留时间(MRT).同时从外周血提取基因组DNA,应用多聚酶链反应-限制性片断长度多态性(PCR-RFLP)测定MDR1第12、21、26号外显子C1236 T、G2677 T/A、C3435 T单核苷酸多态性(SNP).比较3个SNP位点的不同基因型、单倍型间MMF药代动力学参数的差异;比较MPA高暴露组(MPA AUC≥60 mg·h-1·L-1)与MPA低暴露组(MPA AUC＜60 mg·h-1·L-1)间MDR1多态性差异.结果 MDR1第12、21、26号外显子SNP位点突变型纯合子基因型(1236 TT、2677 TT/AA、3435 TT)频率分别为0.368、0.184和0.211.1236 TT基因型受者MPA AUC水平显著高于1236 cc/CT受者,分别为(65.36±11.51)mg·h-1·L-1和(53.33±13.77)mg·h-1·L-1(P=0.032).MPA高暴露组第12号外显子SNP位点上,TT基因型频率显著高于低暴露组,分别为66.7%和15.8%(P=0.013,OR=2.526);T等位基因频率有高于低暴露组的趋势,分别为83.3%和53.3%(P=0.072).结论 具有MDR1第12号外显子TT等位基因的受者,肾移植早期MPA AUC显著高于同一位点其他基因型受者,是MPA高暴露的危险个体.     

尿苷二磷酸葡萄糖醛酸转移酶1A9基因多态性对麦考酚酸浓度的影响

目的 了解中国汉族肾移植受者尿苷二磷酸葡萄糖醛酸转移酶1A9(UGT1A9)基因多态性对体内麦考酚酸(MPA)浓度的影响.方法 使用聚合酶链反应-连接酶检测反应(PCR-LDR)方法对196例汉族肾移植受者的UGT1A9编码基因进行单核苷酸基因多态性(SNP)检测,分别检测C-440T/T-331C、C-2152T、T-275A和T98C突变位点.移植后第28天,通过检测3个时间点(服用吗替麦考酚酯前、服药后0.5 h和2 h)的血浆MPA浓度来推算血浆MPA浓度的时间曲线下面积(MPA-AUC0-12),对SNP和MPA-AUC0-12进行相关性分析.结果 受者的UGT1A9编码基因中,未发现C-2152T、T-275A、T98C突变;C-440T/T-331C突变频率为14.29%(28/196).-440/-331位点CT/TC突变型受者的MPA-AUC0-12为(40.6±11.8)mg·h·L-1,野生纯合(CC/TT)基因型受者的MPA-AUC0-12为(37.6±14.2)mg·h·L-1,两者相比较,差异无统计学意义(P＞0.05).结论 中国汉族肾移植受者的UGT1A9编码基因中,C-2152T、T-275A、T98C突变的发生频率较低,-440/-331位点突变多为杂合基因型.-440/-331位点的SNP与受者血浆MPA浓度没有明显的相关性.     

脓毒症易感性与IRAK-M基因多态性的相关性

目的 探讨脓毒症易感性与IRAK-M基因多态性的关系.方法 选择脓毒症患者82例为实验组,118例健康人群为对照组.应用聚合酶链反应(PCR)-限制性片段长度多态性分析法(RFLP)分析IRAK-M+22148G＞A基因多态性.结果 脓毒症组IRAK-M+22148G＞A位点G/G基因型频率高于对照组(81.7%比28.8%),差异有统计学意义(P＜0.01),G等位基因频率高于对照组(84.1%比33.9%,P＜0.01),差异有统计学意义,脓毒症组肿瘤坏死因子(TNF)-α、白细胞介素(IL)-6水平高于对照组[(843.00±97.34)ng/L比(287.00±79.12)ng/L;(741.00±65.61)ng/L比(194.00±58.47)ng/L],差异有统计学意义(P＜0.05);G/G基因型与脓毒症之间有明显相关(OR=11.03,95%CI:5.55～21.94).结论 IRAK-M+22148G/A基因多态性与脓毒症的易感性相关,G/G基因型者易患脓毒症.

Abstract：

Objective To determine the association between the genetic polymorphisms of IRAK-M and the susceptivity of sepsis. Methods Two candidate gene loci in + 22148G ＞ A patients with 82 sepsis infection and 118 heahhy controls were investigated. The polymorphisms were assessed by the polymerase chain reaction (PCR) and the restrict fragment length polymorphisms (RFLP). Results In sepsis group and control group, the frequency of G/G gene was 81.7% and 8. 8% ( P ＜0. 01 ) and that of G allele was 84.1% and 33.9% ( P ＜0. 01 ), respectively. The levels of tumor necrosis factor (TNF) -α and interleukin (IL) -6 in sepsis group were higher than in control group [ ( 843.00±97.34) vs (287.00±79.12) ng/L;(741.00±65.61) vs (194.00±58.47)ng/L,P＜0.05].The G/G genotype was associated with sepsis (OR=11.03,95% CI=5.55-21.94).Conclusion The genetic polymorphism of +22148 site of IRAK-M gene is associated with the susceptivity of sepsis.The G/G genotype is susceptive to sepsis.     

肾移植受者C YP3A5*3和CYP3A4*18B对他克莫司药动学的影响

目的 探讨肾移植受者细胞色素P4 50酶(CYP)3A5*3、CYP3A4* 18B和CYP3A5-CYP3A4单倍型对他克莫司(Tac)药动学的影响.方法 采用DNA测序法检测61例肾移植受者CYP3A5*3和CYP3A4* 18B基因型.酶联免疫吸附试验测定受者的血Tac浓度,比较术后14d和1、2、3个月时不同基因型受者之间血Tac浓度谷值(G0)、Tac剂量(D)及浓度/剂量(G0/D)的差异.结果 61例中,CYP3A5*3和CYP3A4*18B等位基因突变频率分别为74.6％和26.2％.当CYP3A5表达(*1/*1+*1/*3)者的D是CYP3A5未表达(*3/*3)者的1.3～1.6倍时,未表达者的G0却是表达者的1.1～1.5倍,C0/D是表达者的1.8～2.4倍.CYP3A4* 18B(*1/*18B及*18B/* 18B)基因型者的D是CYP3A4*1/*1基因型者的1.2～1.5倍时,*1/*1基因型者的G0是* 18B基因型者的1.2～1.4倍,G0/D是*18B基因型者的1.5～1.8倍.当CYP3A5-CYP3 A4( AA-AA)者的D是CYP3A5-CYP3A4(GG-GG)者的1.3～1.7倍时,GG-GG的G0是AAAA的1.5～2倍,C0/D是AA-AA的2.5～3倍.当受者G0/D分别位于中位数上下时,CYP3A5、CYP3A4不同基因型和CYP3A5 CYP3A4不同单倍型受者的分布差异较大.结论 肾移植受者CYP3A5*3和CYP3A4* 18B基因多态性对Tac的药动学有显著影响,对CYP3A5 CYP3A4单倍型的分析比单独考虑一种基因型影响更为显著.     

冠心病与内皮型一氧化氮合酶基因多态性的关系

目的 探讨内皮型一氧化氮合酶(eNOS)基因-786T/C,4a4b,894G/T等3个多态性位点与冠心病(CAD)发病相关.方法 对146例中国汉族人群CAD患者和113例正常对照进行遗传学分析,应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)和PCR技术分析2个SNP位点即-786T/C和894G/T,以及1个VNTR位点4a4b,检测各位点基因型和等位基因频率,采用HaploView 4.0及SPSS 13.0软件经x2检验比较两组间各位点基因型及等位基因频率的差异.结果 CAD组中eNOS基因-786T/C位点CC基因型频率为2.0%,4a4b位点4a/4a基因型频率为5.4%,对照组eNOS基因-786T/C位点CC基因型频率为0.0%,4a4b位点4a/4a基因型频率为0.9%,差异有统计学意义(P＜0.05).CAD组和对照组在eNOS基因的894G/T位点等位基因和基因型频率分布差异均无统计学意义(P＞0.05).结论 eNOS基因-786T/C和4a4b多态性与中国汉族人群CAD存在关联,C等位基因和4a等位基因可能是CAD发病的危险因素.eNOS基因894G/T位点与CAD发病无明显相关.

Abstract：

Objective To investigate the relationship between the 3 polymorphisms ( -786T/C,4a4b,894G/T) in endothelial nitric oxide synthase (eNOS) gene and coronary artery disease (CAD).Methods 146 patients with CAD and 113 healthy unrelated individuals in a Chinese Han nation were involved.The genotype and allele frequency of each polymorphism of the eNOS gene in these patients and normal controls were examined by using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) or PCR methods.Genotypes and allele frequency were analyzed by HaploView 4.0 and SPSS13.0 software.Results The frequency of CC genotype of the -786T/C was 2.0%,and that of 4a/4a genotype of the 4a4b was 5.4% in CAD.The frequency of CC genotype of the - 786T/C was 0.0%,and that of 4a/4a genotype of the 4a4b was 0.9% in controls ( P＜0.05 ).There were significant differences in both allele and genotype frequency of -786T/C and 4a4b between CDA group and control group.Between patients with CAD and controls,there were no significant differences in the frequency of the genotypes and alleles of the 894G/T in eNOS gene.Conclusion The - 786T/C and 4a4b polymorphisms of eNOS gene may be associated with CAD.The individuals with C allele of - 786T/C and 4a allele of 4a4b are susceptible to CAD.There is no significant correlation between 894G/T polymorphism in eNOS gene and CAD.     

汉族女性乳腺癌患者has-mir-125a-5p基因的rs12975333位点的单核苷酸多态性及其在癌组织的表达研究

目的 探讨汉族女性乳腺癌患者has-mir-125a-5p基因rs12975333位点单核苷酸多态性(SNP)及has-mir-125a-5p基因在癌组织表达水平与乳腺癌发生发展的关系.方法 选取汉族女性乳腺癌患者289例、乳腺纤维腺瘤49例和相匹配的健康汉族妇女外周血338例,分离淋巴细胞,抽提基因组DNA,采用taqman-MGB探针检测338例乳腺肿瘤及338例健康对照组has-mir-125a-5p的rs12975333位点的单核苷酸多态性;采用茎环Real-time RT-PCR检测289例乳腺癌组织及其正常腺体组织中has-mir-125a-5p的表达水平.结果 乳腺癌组has-mir-125a-5p基因rs12975333位点基因型为GG型273例(94.5%)、GT型16例(5.5%);乳腺纤维腺瘤组及对照组has-mir-125a-5p基因m12975333位点基因型均为GG型;乳腺癌组织has-mir-125a-5p的表达水平(0.19 ±0.04)低于腺体组织(0.37±0.05),差异有统计学意义(P=0.04);携带T等位基因乳腺癌组织中has-mir-125a-5p下调水平较GG基因型表达者更为明显(P=0.022).has-mir-125a-5p的表达降低在发病年龄较晚(P=0.036),ERBB2(P=0.007)、ERBB3(P=0.04)受体表达阴性及存在腋窝淋巴结转移(P=0.001)的乳腺癌组织中更为明显.结论 汉族妇女has-mir-125a-5p基因rs12975333位点的G＞T变异可能与乳腺癌遗传易感性有关;has-mir-125a-5p表达与乳腺癌发生发展相关,是一个潜在的乳腺癌分子标志物.

Abstract：

Objective To investigate the relationship between the single nucleotide polymorphisms (SNPs) in has-mir-125a-5p rs12975333 and the expression of has-mir-125a-5p and clinicopathological cheracteristics of female breast cancer in Han Chinese women. Methods Genomic DNA was extracted from peripheral blood lymphocytes. taqman-MGB assay was used to type breast cancer of 338 cases and 338 controls. Expression levels of has-mir-125a-5p in 289 biopsies were examined using stem-loop real-time RTPCR and the clinicopathological cheracteristics of breast cancer were evaluated. Result The gene frequencies (GG,GT,TT) of rsl2975333 in the patients were GG 273 (94. 5% ), GT 16 (5.5%),TT 0(0%), while in breast fibroadenoma and controls there were GG 49 ( 100% ), 338 (100%). The expression level of has-mir-125a-5p in breast cancer(0. 19 ±0. 04) was lower than that in the matched nontumor adjacent tissue specimens (0. 37 ± 0. 05 ) ( P = 0. 04 ) .The expression level of minor T allele of mature miR-125a in breast cancer patients was lower than that in has-mir-125a-5p-GG carying(P =0.022). The expression of has-mir-125a-5p was down-regulated in primary breast cancer, especially in elder patients ( P = 0. 036) and lymph node metastasis groups (P = 0. 001) and with negative ERBB2 (P = 0. 007), ERBB3 (P =0. 04). Conclusions rs12975333 polymorphisms in has-mir-125a-5p gene may work as a risk factor of breast cancer in Han Chinese women. The altered expression of has-mir-125a-5p might play a role in the pathogenesis and progression of breast carcinoma.     

食管鳞癌遗传易感性与基质金属蛋白酶-1基因多态性的关系

目的 探讨基质金属蛋白酶-1(MMP-1)基因多态性与食管鳞癌发病风险的关系.方法 运用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)分析方法检测450对病例与对照中MMP-1的1G/2G基因多态性.结果 与1G等位基因携带者(包括1G/1G及1G/2G基因型)比较,2G/2G基因型携带者与食管鳞癌显著相关[OR=1.39;95%可信区间(CI):1.06～1.81].此外,食管鳞癌的发病风险在吸炳者及女性中更加显著,其OR及95%CI分别为1.59(1.09～2.31)及1.76(1.05～2.97).结论 MMP-1基因多态性可能在食管鳞癌的发生过程中起到一定作用.

Abstract：

Objective Our study aimed to test the association between the matrix metalloproteinase-1 ( MMP-1) polymorphism and risk of esophageal squamous cell carcinoma ( ESCC ) . Methods We determined the MMP-1 polymorphism in 450 ESCC cases and 450 frequency-matched controls by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). Results We found evidence for a significant association between the 2G/2G genotype and ESCC risk compared with 1G allele,including 1G/1G genotype and 1G/2G genotype [OR = 1. 39;95% confidence interval (CI), 1. 06-1. 81].Furthermore,the increased risk was found to be in smokers (OR,1. 59;95% CI, 1. 09-2. 31) and in female (OR, 1.76;95% CI, 1.05-2. 97). Conclusion Our study suggests that the MMP-1 promoter polymorphism may play a role in the etiology of ESCC.     

肿瘤坏死因子α基因启动子多态性与肾移植术后急性排斥反应的关系

目的　探讨肿瘤坏死因子α(TNF α)基因启动子 3 0 8位多态性在预测肾移植术后急性排斥反应中的意义。　方法　酶联免疫吸附试验检测 3 5例肾移植患者术前外周血细胞分泌的TNF α水平 ,应用限制性片段长度多态性 (PCR RFLP)方法检测TNF α基因启动子 3 0 8位多态性 ,分析其与术后急性排斥反应的关系。　结果　TNF α启动子 3 0 8位为A/A、A/G基因型者TNF α水平分别为(62 4.96± 177.78)pg/ml、(5 44 .3 2± 13 2 .42 )pg/ml,明显高于G/G基因型者的 (2 3 3 .16± 2 5 .3 7)pg/ml,P<0 .0 1。在HLA DR错配情况下 ,TNF α高分泌基因型受者有 5例 (5 0 % )术后发生急性排斥反应 ,而低分泌基因型受者仅有 2例 (8% )发生急性排斥反应 (P =0 .0 12 )。　结论　肾移植受者TNF α基因启动子 3 0 8位多态性与体外细胞因子产生水平有关 ,TNF α高分泌基因型是术后 3个月内发生急性排斥反应的高危因素     

载脂蛋白A1、B基因多态性对非创伤性股骨头坏死发生的影响

目的:探讨载脂蛋白A1、B基因多态性对非刨伤性股骨头坏死(avascular necrosis of the femoral head,ANFH)发生的影响.方法:应用聚合酶链反应对中国北方汉族143例ANFH患者和92例正常人分别扩增含Apo AI基因启动子-75 bp和第一内舍子 83 bp及Apo B基因Eco RI、XbaI和3-VNTR的DNA片段,限制性内切酶酶切扩增产物,琼脂糖凝胶电泳分离基因多态性.结果:Apo A1基因启动子-75 bp处,ANFH患者中A/A基因型频率明显高于正常组(P＜0.01),而G/A基因型频率明显低于正常组(P＜0.01).Apo AI内舍子 83 bp位点,Apo B基因Eco RI、Xba I位点和3-VNTR区域ANFH患者组和正常组基因型及等位基因频率分布无统计学差异.结论:Apo A1基因启动子区域-75bp位点A/A型可能是非创伤性股骨头坏死易感基因之一,但未能发现Apo A1第一内舍子 83 bp位点及Apo B基因Eco RI、XbaI和3-VNTR位点多态性与非创伤性股骨头坏死发生有明显的关系.     

汉族肾移植受者稳定期CYP3A5*3基因多态性与血西罗莫司浓度的相关性

目的 探讨中国汉族稳定期肾移植受者CYP3A5*3和MDR1C3435T基因多态性与血西罗莫司浓度的相关性及个体间差异的影响因素.方法 以112例中国汉族稳定期肾移植受者为研究对象,记录受者性别、年龄、身高、体质量等,采用直接测序法检测CYP3A5*3和MDR1C3435T基因型,化学发光微粒子免疫检测法测定全血西罗莫司浓度谷值(C0).研究血西罗莫司浓度个体间差异的影响因素,比较CYP3A5*3和MDR1C3435T不同基因型受者间血西罗莫司浓度的差异.结果 112例中,CYP3A5*1/*1型10例,*1/*3型49例,*3/*3型53例,*1、*3等位基因的出现频率分别为30.81％和69.19％.MDR13435CC型31例,CT型60例,TT型21例,C、T等位基因的出现频率分别为54.46％和45.54％.受者CYP3A5*3基因型是血西罗莫司浓度的主要影响因素(P=0.000),性别、年龄、身高、术后时间、血肌酐、血红蛋白、联合应用环孢素A和MDR1C3435T基因型对血西罗莫司浓度均无影响(P＞0.05).*1/*1型受者C0·剂量-1·体质量-1为(0.0721±0.0202)μg·L-1·mg-1·kg-,*1/*3型受者为(0.1055±0.0395)μg· L-1 ·mg-1 ·kg-1,*3/*3型受者为(0.1395±0.0537)μg·L-1·mg-1 ·kg-1(P＜0.01).不同基因型受者C0·剂量-1·体质量-1的关系为*3/*3型＞*1/*3型＞*1/*1型,*1/*3型受者是*1/*1型的1.46倍,*3/*3型受者是*1/*1型的1.93倍.结论 汉族稳定期肾移植受者的CYP3A5*3基因多态性是其血西罗莫司浓度的主要影响因素,MDR1C3435T基因多态性则对其无影响.与CYP3A5* 3/*3型受者相比较,CYP3A5* 1/*1、*1/*3型受者为达到目标血药浓度需服用更高剂量的西罗莫司.     

Impact of CYP3A5 and MDR1(ABCB1) C3435T polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients

OBJECTIVE: The objective of this study was to assess the influence of CYP3A5 and MDR1 genetic polymorphisms on tacrolimus pharmacokinetics in Japanese renal transplant recipients. METHOD: The pharmacokinetic parameters of tacrolimus were calculated in steady-state on day 28 after transplantation. Polymerase chain reaction-restriction fragment length polymorphism and direct sequence methods were used for CYP3A5 and MDR1 polymorphisms, respectively. RESULTS: The dose-adjusted area under the concentration-time curve (AUC0-12) was significantly lower among CYP3A5*1 carriers than those bearing CYP3A5*3/*3. (0.570 +/- 0.105 vs 0.865 +/- 0.343 ng.h/mL per mg/kg, P = .00322). The daily tacrolimus dose per body weight was significantly higher in CYP3A5*1 carriers than those of CYP3A5*3/*3 carriers (0.271 +/- 0.110 vs 0.150 +/- 0.056 mg/kg, P = .00016). In this study, a distinction was made between carriers of CYP3A5*1/*1+*1/*3 and CYP3A5*3/*3 to investigate the influence of the MDR1 C3435T mutation on tacrolimus pharmacokinetics. The MDR1 C3435T polymorphisms did not affect any tacrolimus pharmacokinetic parameter in either group. CONCLUSIONS: Renal transplant recipients who were CYP3A5*1 carriers required a higher dose of tacrolimus than CYP3A5*3/*3, indicating a significantly lower dose-adjusted AUC0-12 of tacrolimus. In contrast, MDR1 C3435T polymorphism was not an important factor in tacrolimus pharmacokinetics.     

Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients

BACKGROUND: A body-weight-based dose of tacrolimus often results in marked individual diversity of blood drug concentration. Tacrolimus is a substrate for cytochrome P450 (CYP) 3A5 and p-glycoprotein encoded by CYP3A5 and MDR1 (ABCB1), respectively, having multiple single nucleotide polymorphisms. In this study, we genotyped CYP3A5 A6986G, MDR1 G2677(A/T), and C3435T polymorphisms and investigated the association between these polymorphisms and the pharmacokinetics of tacrolimus in renal transplant recipients. METHODS: Thirty consecutive recipients were enrolled in this study. The pharmacokinetics of tacrolimus was analyzed on day 28 after transplant, when the daily dose was adjusted to the target trough level of 10-15 ng/mL. The polymerase chain reaction-restriction fragment length polymorphism and direct sequence method were used for genotyping the CYP3A5 and MDR1 polymorphisms, respectively. RESULTS: The single tacrolimus dose per body weight was significantly higher in CYP3A5 *1 carriers than CYP3A5 *3/*3 carriers (0.143+/-0.050 vs. 0.078+/-0.031 mg/kg, P<0.001). The dose-adjusted trough level and the area under the concentration-time curve (AUC0-12) were significantly lower in CYP3A5 *1 carriers than CYP3A5 *3/*3 carriers (0.040+/-0.014 vs. 0.057+/-0.024 ng/mL/mg/kg, P=0.015 and 0.583+/-0.162 vs. 0.899+/-0.319 ng.hr/mL/mg/kg, P=0.004), respectively. The MDR1 polymorphism was not associated with any pharmacokinetic parameters. CONCLUSIONS: Kidney transplant recipients with the CYP3A5 *1 allele required a higher daily tacrolimus dose compared with those with the CYP3A5 *3/*3 genotype to maintain both the target trough level and AUC0-12, suggesting that this polymorphism is useful for determining the appropriate dose of tacrolimus.     

Circadian pharmacokinetics of mycophenolic Acid and implication of genetic polymorphisms for early clinical events in renal transplant recipients

BACKGROUND: We investigated the mycophenolic acid (MPA) chronopharmacokinetics and the relation between MPA circadian exposure and the incidence of acute rejection (AR). The association between selected genetic polymorphisms and clinical events or MPA circadian exposure was also studied. METHODS: Thirty recipients were studied one month after renal transplantation. Mycophenolate mofetil (MMF) was administered twice a day at a single dose of 0.5 g in four patients, 0.75 g in eight patients, and 1 g in 18 patients. RESULTS: The daytime area under the concentration-time curve (AUC0-12) was larger than the nighttime AUC0-12 (55.09 vs. 50.54 microg.hr/ml, P=0.049). The Cmax and tmax of MPA after the morning dose were respectively higher and shorter than those after the night dose. Seven patients (23.3%) had AR episodes. The MMF single dose per body weight (12.46 mg/kg in patients with AR vs. 16.99 in patients without AR), daytime and nighttime AUC0-12 (32.41 vs. 62.00 and 24.44 vs. 57.88 microg.hr/ml) and morning trough level of MPA (1.03 vs. 3.83 microg/ml) were significantly lower in patients with AR than in those without AR. The percentage of patients requiring diminished dose of MMF due to diarrhea was higher among patients with the multidrug resistance 1 (MDR1) C3435T T allele than among those with the CC genotype (P=0.049). CONCLUSION: MPA pharmacokinetics showed circadian variations, and a lower MPA AUC in both daytime and nighttime was associated with the occurrence of AR in the early stage after renal transplantation. The MDR1 C3435T polymorphism might be associated with diarrhea due to MPA.     

Mycophenolic acid pharmacokinetics in stable pediatric renal transplantation

Mycophenolate mofetil (MMF) is given to children in fixed doses based either on body weight or body surface area. There are data indicating mycophenolic acid (MPA) blood levels should be monitored in the early period of transplantation. However, there is little information regarding MPA pharmacokinetics (PK) in stable pediatric recipients. We evaluated MPA-PK in 20 stable renal transplant children (11.7+/-1.9 years) under long-term (46+/-31 months) MMF (26.1+/-7 mg/kg per day or 785+/-183 mg/m(2) per day) therapy plus prednisone and cyclosporin A (n=16), tacrolimus (n=3), or MMF/prednisone (n=1). Total MPA levels were measured using the EMIT-MPA assay at 0, 1, 2, 3, 4, 6, and 8 h after an oral dose of MMF. The level at 12 h was considered equal to the trough level for AUC(0-12) calculation. Mean C(0), C(max), AUC (0-12), and T(max )were 3.46+/-1.32, 13.5+/-0.58 microg/ml, 63.2+/-24.4 microg x h/ml, and 1.3+/-0.6 h, respectively. Six (30%) children were considered to have an adequate exposure (36-54 microg x h/ml) to MPA, 11 (55%) showed an AUC(0-12 )>54 microg.h/ml, and 3 (15%) showed an AUC(0-12 )<36 microg x h/ml. A C(max )>/=10 microg/ml was seen in 13 (65%) children. MMF dose did not correlate with AUC(0-12) or C(max). The combination of variables C(0), C(1), and C(4 )provided an equation to predict exposure (r(2)=0.75) where AUC(0-12)=12.62+(7.78 x C(0))+(0.90 x C(1))+(1.30 x C(2)) (P<0.001). The use of MMF without monitoring MPA blood levels may cause unnecessary overexposure to the drug in stable pediatric recipients.     

不同霉酚酸剂型在儿童肾移植不同年龄段的暴露差异

目的  探讨儿童肾移植术后服用不同霉酚酸（MPA）制剂在≤12岁与 > 12岁年龄段的暴露差异。方法  回顾性分析73例接受心脏死亡器官捐献（DCD）儿童肾移植受者的临床资料,术后免疫抑制方案均为MPA+他克莫司+糖皮质激素,按照MPA剂型分为A组（37例,服用吗替麦考酚酯胶囊）、B组（28例,服用麦考酚钠肠溶片）和C组（8例,服用吗替麦考酚酯分散片）。并根据移植时患者年龄分为≤12岁年龄段和 > 12岁年龄段。计算不同药物剂型每日给药剂量,采用酶放大免疫法检测MPA血药浓度（C）与曲线下面积（AUC）,比较各组不同时间点和两个年龄段的MPA血药浓度,分析受者术后肾功能恢复情况及并发症发生情况。结果  A、B、C组给药剂量和各时间点血药浓度比较,差异均无统计学意义（均为P > 0.05）。≤12岁年龄段MPA-C_{4 h}、AUC均高于 > 12岁年龄段,差异均有统计学意义（均为P < 0.05）。B组≤12岁年龄段MPA-C_{4 h}高于 > 12岁年龄段,差异有统计学意义（P=0.016）。B组≤12岁年龄段MPA-C_{4 h}较A组和C组高,但差异无统计学意义（P=0.080）。3组急性排斥反应和感染发生率差异均无统计学意义（均为P > 0.05）。结论  不同年龄段儿童肾移植术后服用不同MPA制剂有不同的暴露率,≤12岁儿童肾移植受者暴露率较 > 12岁儿童有升高的趋势,但主要表现在服用麦考酚钠肠溶片的受者中。因此,监测MPA的暴露水平是必要的,对调整不同剂型药物用量具有较大的指导意义。     

Pharmacokinetics of mycophenolic acid in kidney transplant patients receiving sirolimus versus cyclosporine

INTRODUCTION: Mycophenolic acid (MPA) pharmacokinetics exhibit large variability in transplant recipients and may be altered due to concurrent immunosuppressants. Little is known about the influence of sirolimus (SRL) on MPA pharmacokinetics in kidney transplant patients. METHODS: We studied the areas under concentration-time curves (AUC) for MPA in 15 patients receiving immunosuppression combining SRL with mycophenolate mofetil (MMF). The pharmacokinetic measurements were performed in all patients using three MMF dosing regimens (0.5 g twice a day, 0.75 g twice a day, 1 g twice a day). Similar blood AUC profiles were also sampled from 12 patients treated with a fixed dose of MMF 1 g twice a day and cyclosporine (CsA). MPA was measured using HPLC; the AUC0-12 of MPA was determined by the trapezoidal method using four sampling time points: C0, C1, C3, C5. RESULTS: While patients on SRL were receiving 0.75 g MMF twice a day, mean AUC0-12 and C0 values of MPA were comparable to those of patients receiving CsA and 1 g MMF twice a day (54.1 +/- 17.6 and 3 +/- 1.87 vs 51.7 +/- 16.7 mg.h/L and 2.76 +/- 1.57 mg/L, respectively). On the other hand, 0.5 g MMF twice a day with SRL therapy resulted in AUC0-12 and C0 values of MPA of 32.3 +/- 12.6 mg.h/L and 2.32 +/- 1.72 mg/L, respectively, whereas, 1 g MMF twice a day with SRL resulted in AUC0-12 and C0 values of MPA of 70.9 +/- 19.3 mg.h/L and 4.7 +/- 2.44 mg/L, respectively. CONCLUSIONS: These findings demonstrate that MPA exposure in the presence of SRL is higher than that with CsA. It appears that the MMF dose should be reduced to 0.75 g twice a day in patients receiving SRL to obtain AUC0-12 of MPA levels comparable to that in patients treated with CsA and MMF 1 g twice a day.     

Longitudinal evaluation of mycophenolic acid pharmacokinetics in pediatric kidney transplant recipients. The role of post-transplant clinical and therapeutic variables

Abstract:  This longitudinal study assessed the influence of post-transplant clinical and therapeutic variables in 50 kidney transplant recipients aged 2–19 yr receiving a triple immunosuppressive regimen consisting of cyclosporine microemulsion (CsA), steroids and MMF (300–400 mg/m² body surface area twice daily), the full pharmacokinetic profile (10 points) of which was investigated on post-transplant days 6, 30, 180 and 360. Total plasma MPA was measured by Enzyme Multiplied Immunoassay Technique. CsA therapeutic drug monitoring (TDM) was performed via C2 blood monitoring, while MPA TDM via C0. MPA Cmax, tmax, AUC0-12 and AUC0-4 pharmacokinetic profile changed significantly during the first post-transplant year. C0 was a poor predictor of the total MPA exposure [as measured by the area under the concentration-time curve AUC)], while a truncated AUC was a good surrogate of the 12-h profile (r = 0.91; p < 0.001) Graft function and cyclosporine therapy influenced MPA pharmacokinetics, as shown by the univariate and multivariate analyses. We conclude that because after transplantation MPA exposure varied over time, a strict TDM is advisable in the pediatric population.     

Comparative pharmacokinetic study of two mycophenolate mofetil formulations in stable kidney transplant recipients

We compared steady-state pharmacokinetics of mycophenolate mofetil (MMF) - Myfenax(?) (Teva) and CellCept(?) (Roche) - in stable kidney transplant recipients (KTRs). This was an international, multi-centre, randomized, open-label, two-treatment, two-sequence crossover study with a 3-month follow-up. We included KTRs at least 12 months post-transplantation with stable renal graft function for at least 3 months. The maintenance treatment consisted of MMF in combination with tacrolimus with or without steroids. At the end of the two treatment periods, 6-h or 12-h PK studies of mycophenolic acid (MPA) were performed. A total of 43 patients (mean age: 50.7 ± 13.5 years; 19 females, 24 males) were randomized. Estimates of test to reference ratios (90% CIs) were 0.959 (0.899; 1.023) h*μg/ml for AUC((0-tau)) and 0.873 (0.787; 0.968) μg/ml for C(max). Estimates for AUC((0-6h)) were 0.923 (0.865; 0.984) h*μg/ml and 0.985 (0.877; 1.106) μg/ml for C(min). Thus, AUC((0-tau)), AUC((0-6h)), and C(min) of MPA were within the predefined margins. C(max) was somewhat outside of these margins in this set of patients. The numbers and types of adverse events were not different between the two treatments. The steady-state pharmacokinetics of MPA as well as adverse events are comparable for Myfenax(?) and CellCept(?) in tacrolimus-treated stable KTRs.