他克莫司浓度在移植患者全血、血浆与血细胞中的相关性研究

目的:研究移植患者全血、血浆与血细胞中他克莫司浓度的相关性,并分析移植类型及年龄对三者间他克莫司浓度相关性的影响,为临床合理用药提供参考。方法:随机选取我院20例移植术后使用他克莫司抗排异治疗并进行血药浓度监测的患者,根据移植类型分为肾移植组和肺移植组(各10例),根据年龄分为20～40岁组、41～60岁组和61～80岁组(分别有4、9、7例)。收集患者血药浓度监测的残血,采用化学发光微粒子免疫分析法(CMIA)检测全血中他克莫司谷浓度,并采用超高效液相色谱-串联质谱(UPLC-MS/MS)法同时检测血浆及血细胞中他克莫司浓度。应用散点图矩阵和Spearman秩相关性分析全血与血浆、全血与血细胞、血浆与血细胞中他克莫司浓度的相关性,以及移植类型、年龄对三者间他克莫司浓度相关性的影响。结果:全血与血浆中他克莫司浓度相关性(r=0.623,P<0.01)略强于全血与血细胞中他克莫司浓度的相关性(r=0.591,P<0.01),血浆与血细胞中他克莫司浓度相关性相对较弱(r=0.497,P<0.05)。移植类型、年龄对全血、血浆、血细胞三者间他克莫司浓度相关性均有影响,肾移植组患者全血、血细胞、血浆三者间他克莫司浓度相关性均较弱(r均<0.5),且弱于肺移植组患者;20～40岁组患者全血、血浆、血细胞三者间他克莫司浓度相关性也均较弱(r均<0.3),且均弱于41～60岁组、61～80岁组患者。结论:移植术后患者全血、血浆与血细胞三者间他克莫司浓度的相关性均不强,尤其是肾移植患者和20～40岁年龄段患者,应加强对其排斥反应和不良反应的监测。     

五酯胶囊与他克莫司合用对肾移植受者的成本与效果评估研究

目的 研究五酯胶囊(肝细胞损伤拮抗剂)与他克莫司胶囊(免疫抑制剂)合用,对肾移植受者他克莫司血浓度及其费用的影响.方法 64名肾移植患者,随机分为单用他克莫司组和他克莫司+五酯胶囊合用组,连续服药6个月.以他克莫司全血浓度及肝、肾功能生化检测指标,作为临床评价指标;同时计算患者用他克莫司的费用.结果 与合用前比较,合用五酯胶囊3,6个月后,患者他克莫司全血浓度、他克莫司血浓度/剂量比值,均明显增加(P<0.01或P<0.05),与对照组比较有显著性差异(P<0.01或P<0.05).五酯胶囊与他克莫司合用,对肝、肾功能无明显影响.合用五酯胶囊后,每位患者每年可节约购买他克莫司费的40%～60%,每年节省费用约合1.4～2.5万元.结论 五酯胶囊能明显升高肾移植受者他克莫司血浓度;五酯胶囊与他克莫司合用,可减少他克莫司用药量,明显节省他克莫司费用.     

他克莫司全血样品保存时间和温度考察

目的:考察他克莫司全血样品的保存温度和保存时间,为外地患者通过运输样品方便监测他克莫司浓度提供依据.方法:取测定他克莫司血浓度的全血样品10份,测定他克莫司浓度后将样品立即分成2份,一份置于(25±3)℃室温保存,另一份置于4℃冰箱冷藏,分别在3,5,7d重复测定他克莫司浓度,使用PEMS软件对室温保存和冰箱冷藏3,5,7d后测得浓度分别对新鲜样品浓度进行配对t检验,计算配对百分比平均值和RSD.结果:P值分别为0.9295,0.7965,0.7336和0.9193,0.9692,0.8670,配对百分比平均值最大为99.85％,最小为95.02％,RSD均＜5％.结论:他克莫司全血样品室温保存或冰箱冷藏7d,浓度变化差异无统计学意义(P＞0.05)且在免疫分析方法允许范围内(RSD＜5％),样品在4～25℃条件下7d内运输至有条件实验室监测他克莫司浓度,结果基本可靠.     

肾移植患者全血他克莫司浓度监测结果分析

目的：探讨肾移植患者全血他克莫司浓度的治疗窗及对血常规和肝肾功能的影响。方法：MEIA法监测全血他克莫司谷浓度。对近4年来390例次肾移植患者全血他克莫司浓度，及他克莫司对血常规和肝肾功能的影响进行分析。结果：390例次全血他克莫司浓度中377例次（80．8％）在3～15μg·L^-1的范围内。移植后6个月内，全血他克莫司浓度差异较大。随着移植时间延长，全血他克莫司浓度逐步降低。在治疗剂量内，他克莫司对肾移植受者的血常规和肝肾功能无明显影响。结论：全血他克莫司谷浓度的治疗窗：术后1～3月为5～15·L^-1，第4～6月为5～10·L^-1，〉6个月为3～10·L^-1。他克莫司对肾移植受者的血常规和肝肾功能无明显影响。     

不同给药途径下质子泵抑制药对肾移植患者免疫抑制药血药浓度的影响

摘要：目的:研究不同给药方式给予质子泵抑制药（PPIs）对肾移植术后患者吗替麦考酚酯及他克莫司血药浓度的影响。方法:利用均相酶免疫法检测肾移植患者口服及静脉给予PPIs时,吗替麦考酚酯及他克莫司的血药浓度。分析两种给药方式对吗替麦考酚酯及他克莫司血药浓度的影响。结果:与静脉给予PPIs时相比,口服给予PPIs时霉酚酸（MPA）的谷浓度（C0）平均升高1.36倍,给药后30 min的血浓度(C30)平均升高1.48倍,120 min药时曲线下面积(AUC0-120)平均升高1.17倍,他克莫司谷浓度平均升高1.54倍,差异均有统计学意义（P＜0.05）。MPA给药后120 min的血浓度(C120)平均升高了1.04倍,但差异无统计学意义（P＞0.05）。静脉给予PPIs时他克莫司谷浓度达标率为24.39%,而口服给予时为85.36%,差异有统计学意义（P＜0.01）。结论:临床药师监测血药浓度对肾移植术后患者进行药学监护,吗替麦考酚酯的血药浓度和他克莫司的血药浓度达标率均有明显提高,在临床药物治疗过程中起到了重要作用。     

移植后高血压与他克莫司剂量及血药浓度的关系

目的:调查肾移植患者服用他克莫司后高血压的发生率,并探讨移植后高血压与他克莫司的服用剂量、血药浓度及血药浓度/剂量的相关性。方法:选取以他克莫司进行治疗的肾移植患者200例,测量患者的血压。然后从中随机抽取53例高血压患者和53例正常血压患者,待患者服用他克莫司至少3d后,运用微粒子酶免疫分析(MEIA)法测定他克莫司谷浓度,分析他克莫司剂量、血药浓度与血压水平的相关性,并比较两组患者的他克莫司剂量、血药浓度及血药浓度/剂量的差异。结果:在200例肾移植患者中,104例患者(52.0%)患有移植后高血压;他克莫司日剂量与患者的SBP呈正相关(r=0.216,P<0.05),而剂量与DBP,血药浓度与血压水平均无相关性;高血压组他克莫司的服用剂量明显高于正常血压组[(3.11±1.49)mg/d∶(2.42±1.07)mg/d,P<0.05];谷浓度两组间比较差异无统计学意义(P>0.05);高血压组患者的谷浓度/剂量明显低于正常血压组[(2.94±1.57)ng.d/mg.mL∶(3.95±3.02)ng.d/mg.mL,P<0.05]。结论:肾移植患者的SBP与他克莫司日剂量具有明显相关性,服用更高剂量他克莫司的患者更易发生高血压。     

CYP3A基因多态性与他克莫司血药浓度的相关性研究

目的:探讨肾移植术后口服免疫抑制剂他克莫司的剂量及其全血谷浓度个体差异的原因。方法:用基质辅助激光解吸电离飞行时间质谱技术对60例肾移植稳定期患者的CYP3AP1、CYP3A5*3的基因型进行检测,并分析各项临床指标对他克莫司血药浓度的影响。结果:60例肾移植患者中,性别、年龄、体质量、身高、激素剂量、血清肌酐对他克莫司浓度/(剂量×体表面积)比值并没有显著影响(P>0.05),术后时间和CYP3AP1、CYP3A5*3是主要影响因素(P<0.05)。CYP3AP1他克莫司浓度/(剂量×体表面积)比值高低依次为GG组相似文献   

CYP3A4* 1G基因多态性对肾移植受者他克莫司给药剂量及血药浓度影响的系统评价

目的系统评价CYP3A4*1G基因多态性对肾移植受者他克莫司日剂量、全血谷浓度及浓度剂量比的影响。方法计算机检索Em Base、Pub Med、Cochrane Library、CNKI、万方及Sino Med等数据库,收集CYP3A4*1G基因多态性对他克莫司给药剂量及血药浓度影响的研究,用Revman 5.2软件进行Meta分析。结果共纳入7项研究(中文5篇,英文2篇),包括750名成年肾移植受者。Meta分析结果表明,CYP3A4*1G组他克莫司日剂量显著高于CYP3A4*1/*1组患者(P<0.05)。亚组分析显示,肾移植术后14 d内,2组他克莫司日剂量比较差异无统计学意义(P>0.05);而术后1个月及2~3个月时,CYP3A4*1G组他克莫司日剂量均显著高于CYP3A4*1/*1组(均P<0.05),他克莫司全血谷浓度及浓度剂量比均显著低于CYP3A4*1/*1组(均P<0.05)。结论 CYP3A4*1G基因多态性显著影响肾移植受者他克莫司日剂量及其血药浓度。     

微粒子酶免疫法监测肝移植术后他克莫司血药浓度

目的:为了避免他克莫司的不良反应,对使用他克莫司的肝移植患者实施治疗药物监测。方法:用微粒子酶免疫法测定全血他克莫司谷浓度,并对他克莫司谷浓度的监测结果进行回顾性分析。结果:当肝移植患者被给予他克莫司、泼尼松和硫唑嘌呤时,他克莫司谷浓度与剂量之间存在正相相关。为了得到理想的效果和最小的毒性,他克莫司的全血药物浓度在肝移植后的90d内应维持在10～20μg·L~(-1),90d后在5～15μg·L~(-1)。结论:对于肝移植患者,他克莫司的全血药物浓度监测是很必要的,而且对于减少毒性和排斥反应的危险性是很有帮助的。     

肾移植患者他克莫司的血药浓度与CYP3A5*3基因多态性的关系

目的研究CYP3A5*3基因突变对他克莫司全血谷浓度(经体表面积剂量校正)、不良反应和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227例肾移植患者CYP3A5*3基因型,比较不同基因型患者之间他克莫司的全血谷浓度、不良反应和急性排斥反应发生率的差异。结果 CYP3A5*3基因多态性中,*1/*1型18例(7.9%),*1/*3型81例(35.7%),*3/*3型128例(56.4%)。肾移植术后3个月内,*1/*1型、*1/*3型和*3/*3型患者的他克莫司全血谷浓度经体表面积剂量校正后分别为1.84±0.71、2.06±0.83和4.11±2.13,*1/*1型和*1/*3型之间差异未见统计学意义(P>0.05),但与*3/*3型之间差异均有高度统计学意义(P<0.01)。组间不良反应和急性排斥反应发生率之间差异无统计学意义(P>0.05)。结论肾移植患者的CYP3A5*3基因多态性与他克莫司的服用剂量密切相关,对含CYP3A5*3等位基因的患者在应用他克莫司时应较常规减少用药剂量并注意不良反应的发生,而对CYP3A5野生型的肾移植患者应适当增加服药次数以降低排异反应。     

Effects of ciclosporin on whole blood chemiluminescence of renal transplant patients

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环孢素对肾移植病人全血化学发光的影响

AIM: To examine the possible inhibitory role of ciclosporin (Cic) on luminol-dependent chemiluminescence (CL) of whole blood in renal transplant patients. METHODS: Luminol-dependent CL was used to measure active oxygen species generation in respiratory burst of whole blood stimulated by zymosan A. Fluorescence polarization immunoassay was used to monitor the blood concentration of Cic. RESULTS: CL values of Cic group (n = 50) decreased in comparison with those of normal group (n = 10) (P < 0.01). The blood concentration of Cic was negatively related to CL value (P < 0.01). The serum of renal transplant patients directly inhibited respiratory burst of peritoneal macrophages of rats in a concentration-dependent manner. CONCLUSION: Cic inhibits the phagocytic activity of neutrophils in renal transplant patients.     

Population pharmacokinetics of tacrolimus in whole blood and plasma in asian liver transplant patients

OBJECTIVES: The objectives of this study were to develop population pharmacokinetic models of tacrolimus in an Asian population with whole blood and plasma drug concentration data, to compare the variability of the pharmacokinetic parameters in these two matrices and to search for the main patient characteristics that explain the variability in pharmacokinetic parameters. STUDY DESIGN: Prospective pharmacokinetic assessment followed by model fitting. PATIENTS: Whole blood samples from 31 liver transplant patients in a local hospital receiving oral tacrolimus as part of their immunosuppressive therapy were assessed. Plasma samples from 29 of the 31 patients were also evaluated. Concentrations of tacrolimus in whole blood and plasma were determined by an electrospray high-performance liquid chromatography with tandem mass spectrometry. Two hundred and thirteen whole blood and 157 plasma tacrolimus concentrations were used for building two nonlinear mixed-effects population models to describe the disposition of tacrolimus in whole blood and plasma, respectively. Covariates that were investigated included demographic characteristics, biological markers of liver and renal functions, corticosteroid dose and haematological parameter. RESULTS: A one-compartment model was used to describe the whole blood and plasma concentration-time data of tacrolimus after oral administration. For the whole blood population model, the population estimates of the first-order absorption rate constant (k(a)), apparent clearance based on whole blood concentration after oral administration (CL(B)/F) and apparent volume of distribution based on whole blood concentrations after oral administration (V(d,B)/F) were 2.08h(-1), 14.1 L/h and 217L, respectively. The coefficient of variations (CVs) of interpatient variabilities in CL(B)/F and V(d,B)/F were 65.7% and 63.8%, respectively. Bodyweight, liver and renal function influenced CL(B)/F, while height and haematocrit influenced V(d,B)/F. The residual (unexplained) variability was 34.8%. For the plasma population model, the population estimates of the k(a), apparent clearance based on plasma concentrations after oral administration (CL(P)/F) and apparent volume of distribution based on plasma concentrations after oral administration (V(d,P)/F) were 5.21h(-1), 537 L/h and 563L, respectively. The CVs of interpatient variabilities in CL(P)/F and V(d,P)/F were 96.0% and 105.4%, respectively. Bodyweight was found to influence CL(P)/F, while the erythrocyte-to-plasma concentration ratio influenced V(d,P)/F. The residual (unexplained) variability was 49.8% at the mean plasma concentration of 1.1 ng/mL. CONCLUSIONS: Whole blood and plasma population pharmacokinetic models of tacrolimus in Asian adult and paediatric liver transplant patients were developed using prospective data in a clinical setting. This has identified and quantified sources of interindividual variability in CL(B)/F, V(d,B)/F, CL(P)/F and V(d,P)/F of tacrolimus in Asian liver transplant patients. Information derived from the whole blood population model may subsequently be used by clinicians for dosage individualisation through Bayesian forecasting.     

他克莫司在中国肾移植患者中的群体药物动力学研究

本研究旨在考察口服他克莫司(tacrolimus)在中国肾移植患者中的群体药物动力学特征并探讨群体药物动力学参数和相关因素间的关系。研究中回顾性搜集了58例肾移植患者的802份他克莫司稳态全血样本资料。患者随机分为模型建立组(41例)和模型验证组(17例)。用非线性混合效应模型(NONMEM)程序中的一级评估法(first-order estimation，FO)对模型建立组的数据进行分析。计算清除率(CL/F)、表观分布容积(V/F)的群体典型值，定量评价人口统计学指标、生化指标和合并用药等固定效应因素对药物动力学参数的影响。单室一级吸收和消除模型能够较好地拟合数据。最终模型包含了移植术后时间(POD)、红细胞压积(HCT)、谷草转氨酶(AST)、合并使用佩尔地平(NICA)和地尔硫(DIL)等对CL/F的影响。用模型验证组数据进行验证的结果表明观测值和模型预测值之间没有明显的偏倚，模型的稳定性和准确度较好。CL/F和V/F的群体典型值分别为21.7 L·h^-1和241 L；相应的个体间变异分别为41.6%和49.7%。观测值与预测值之间的残差SD为2.19 μg·L^-1。本文建立的模型可以为临床他克莫司剂量选择提供一定参考。     

Tacrolimus whole blood concentrations correlate closely to side-effects in renal transplant recipients

AIMS: To evaluate the relationship between tacrolimus whole blood concentrations and side-effects and rejections in 14 renal transplant recipients. METHODS: Tacrolimus was measured by MEIA in whole blood in samples collected repeatedly during the first year after transplantation. Retrospectively, tacrolimus trough concentrations on the days with adverse events (n=172) or rejection (n=28) were related to the total distribution of the concentration values (n=656). RESULTS: Side-effects (one or more) were noted in connection with 76% of tacrolimus concentrations above 30 ng ml-1, with 41% of concentrations within the interval of 20-30 ng ml-1, with 26% of the concentrations within the interval of 10-20 ng ml-1 and with only 5.3% on the concentrations lower than 10 ng ml-1. No relation to the tacrolimus concentration was seen for rejection episodes. CONCLUSIONS: We conclude that therapeutic drug monitoring may be helpful in the management of tacrolimus therapy and that tacrolimus whole blood trough concentrations (MEIA) should preferably be kept below 20 ng ml-1 to avoid side-effects, such as nephro-and neurotoxicity and infections. The lower limit of the therapeutic range has yet to be defined.     

肾移植术后他克莫司血药浓度的临床观察

目的 探讨他克莫司在肾移植患者的临床疗效及术后的血药浓度.方法 肾移植术患者54例,随机分为观察组和对照组,对照组口服环孢素A,观察组口服他克莫司.比较研究两组的临床疗效,并检测观察组的不同时期的血药浓度.结果 与对照组相比,观察组血清直接胆红素（D-BILI）、总胆红素（T-BILI）浓度显著降低,急性排斥反应和感染比率明显降低,差异均有统计学意义（P〈0.05）;同时,观察组患者他克莫司血药浓度在术后不同时期均有差别.结论 他克莫司有望发展为主要的免疫抑制剂,对其血药浓度影响因素的进一步研究,将有利于为临床器官移植患者提供合理的用药方案.     

肾移植受者血药浓度监测与最佳浓度选择

目的:寻找环孢素A(CsA)在肾移植受者三联免疫抑制用药方案中的最佳浓度.方法:用特异荧光偏振免疫法测定82例患者全血环孢素A的浓度,比较不同剂量组(各41例)患者肾移植术后CsA浓度高低、急性排斥反应和毒性反应发生率以及移植患者的人/肾生存率.结果:高浓度组在1年内总的急性排斥反应发生率为16.8%,低浓度组为18.2%,两组间差异无显著性(P＞0.05),高低浓度组患者1年内毒性反应发生率分别为32.1%和16.4%(P＜0.01),人/肾生存率分别为85.2%/82.8%和92.1%/90.9%(P＜0.05).结论:实验结果表明,低浓度组并不增加急性排斥反应的发生率,但明显降低毒性反应发生率以及移植患者的人/肾死亡率.     

Tacrolimus and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors: An interaction study in CYP3A5 non-expressors, renal transplant recipients

Objectives:

Atherosclerosis is a significant factor affecting long-term outcome in renal transplant recipients. Studies have been conducted to determine the pharmacogenomic pathways involved in statin efficacy, efficiency, and adverse effect likelihood. However, little is known about the influence of statins on tacrolimus kinetics. The aim of this study was to investigate possible pharmacological interactions between tacrolimus and statins in CYP3A5 non-expressors, renal transplant recipients.

Materials and Methods:

Twenty-four patients, treated with tacrolimus (n=24), methylprednisolone (n=24), and mycophenolate mofetil (n=19)/azathioprine (n=1)/everolimus (n=4), participated in the study. After an observation time of 112±36 days, statins, namely, atorvastatin (n=12), simvastatin (n=8), pravastatin (n=2), or fluvastatin (n=2), were administered for additional 101±34 days. DNA was extracted from whole blood sample and polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for CYP3A5 genotyping. Student''s t-test and Mann-Whitney test were used to test the significance of difference in variables that passed or did not pass Kolmogorov''s normality test, respectively.

Results:

No statistically significant difference was observed in tacrolimus daily dose, concentration, concentration/dose ratio, and volume of distribution before and during the administration of statins. Statistically significant decrease in serum cholesterol was observed after initiation of statins. Renal and hepatic function remained unchanged and no skeletal muscle abnormalities were reported.

Conclusions:

The results of this study show that tacrolimus and statins do not interact in terms of efficacy, efficiency, and adverse effect likelihood. No significant clinical interaction or effect was observed, even with the use of atorvastatin or simvastatin, which are metabolized by CYP3A4 such as tacrolimus.     

他克莫司对9例肾移植病人的药物动力学

目的 :研究单剂量口服他克莫司在肾移植病人体内药物动力学。方法 :9名肾移植病人单剂量口服他克莫司 2～ 3mg后 ,于 0 ,0 .3 3 ,0 .66,1,1.5 ,2 ,3 ,4,6,8,10 ,12h分别取外周静脉血 ,用微粒子酶免分析法 (MEIA)测定全血药物浓度 ,3P97模拟药物动力学模型 ,计算有关药物动力学参数。结果 :他克莫司符合二室模型 ,T12 α(0 .6± 0 .5 )h ;T12 β(13± 2 1)h ;Cmax(15± 7) μg·L- 1;Tmax(1.6±1.4)h ;V/F(15 6± 95 )L ;AUC0→∞(14 0± 166) μg·h·L- 1;Tlog(0 .3 0± 0 .0 5 )h ;Cssmin(10± 7) μg·L- 1。结论 :9例肾移植病人单剂量口服他克莫司后药物动力学参数与国外文献报道基本相符。