肝肾移植受者环孢素稳态药动学比较

目的比较肝肾移植受者环孢素（CsA）临床药动学差异。方法采用荧光偏振免疫法测定16例肝肾移植受者服用CsA后不同时间点的血药浓度，计算药动学参数。结果CsA代谢呈二房室开放模型。肝移植受者较肾移植β显著减小，T1／2日、T1／2a延长，tmax和达平均稳态血药浓度的时间（tcos）后移。结论CsA药动学参数个体差异大。肝移植受者的CsA分布和消除较肾移植显著减慢，易发生蓄积。     

411例肾移植患者口服环孢素A群体药动学研究

目的:考察肾移植患者口服环孢素A的群体药动学特征。方法:用NONMEM软件,针对411例门诊肾移植患者(建模组274例,验证组137例)的1 122个时间数据进行群体药动学体内分析。结果:群体最大消除常数典型值(Vm)为:Vm(mg·d-1)=θ1·(DAY／800)θ4·(BW／60)θ6·(AGE／42)θ7·(ALB／40)θ10·(DB／5)θ11·(ALT／20)θ13·(TG／1．8)θ15·θ16(AST>50),或Vm(mg·d-1)=θ1·(DAY／800)θ4·(BW／60)θ6·(AGE／42)θ7·(ALB／40)θ10·(DB／5)θ11·(ALT／20)θ13·(TG／1．8)θ15(AST≤50);米氏常数Km(μg·L-1)=θ2·(DOSE／200)θ3·(DAY／800)θ5·(BW／60)θ6·(AGE／42)θ9·(CR／110)θ12·(ALT／20)θ14;Vm和Km的个体间变异分别是25．4和14．2;个体自身的变异是18．7。结论:肾移植患者每日口服环孢素剂量和术后时间对米-曼氏模型参数影响较大,用群体药动学模型分析常规监测数据可为临床患者提供用药依据。     

NONMEM法分析肾移植患者环孢素A的群体药动学

用HPLC和FPIA法(单克隆抗体)测定全血中环孢素A(CsA)浓度,收集临床60例肾移植患者牛奶送服CsA后浓度数据281点,应用NONMEM程序一步法估算其群体药动学参数,并定量地分析体重、年龄、性别,长期用药对清除率的影响。按口服吸收一室开放模型估算的群体药动学参数为:清除率CL(L·h^-1)、表现分布容积V_d(L)和口服吸收速率常数K_a(h^-1)分别等于59.8,227及1.28,其个体间变异Q_CL(%),Q_VL(%)及Q_Ka(%)分别为30.27,29.02和75.10,浓度观察值与模型预测值的残差变异Q_E(%)等于31.19固定效应与CL的定量关系为:以体重的0.03倍加法调整,男性较女性患者增加4.31,长期用药患者下降12.7。     

肾移植术后早期国产环孢素药动学的临床研究

目的:探讨肾移植受者术后早期服用国产环孢素的药动学变化特点。明确环孢素各时点血药浓度与时间-曲线下面积(AUC)的相关关系。方法:43例肾移植受者始服环孢素6 mg·kg~(-1)·d~(-1)7 d后,按不同品种分A组18例,B组15例,C组10例。3组分别于服药即刻,服药后1,2,3,4,5,6,8,10,12 h抽血查环孢素浓度(以C_0、C_1、C_2……C_(12)表示),比较不同品种药动学的变化特点。然后,用逐步回归分析法计算环孢素的总体C_0、C_2、峰浓度C_(max),达峰时间(T_(max)),AUC以及各种指标的变异系数,并计算各浓度值与AUC的相关关系。结果:3种国产环孢素在使用相同剂量时,C_0,C_2,C_(max),T_(max),AUC差异均无显著性,具有同质性。合并分析后,总体值C_0为(215.2±113.0)μg·L~(-1),总体C_(max)=C_2为(1024.8±378.7)μg·L~(-1),达峰时间(2.0±0.9)h,平均2h,AUC为(5106.4±1471.8)μg·h·L~(-1)。抽血检测的10个时点浓度中,C_1、C_2、C_3、C_4、C_6与AUC的相关性有显著性,其中C_2偏相关系数0.96最大,而变异系数(34.9％)相对较小。C_0不仅变异系数(52.8％)较大,且与AUC的相关性亦不显著。结论:国产环孢素总体峰浓度为C_2,与AUC具有较好的相关性,对AUC的变化影响大。可以将C_2作为临床一个常规的环孢素浓度监测指标。     

家兔体内环孢素A微囊栓剂的药动学

目的 :制备环孢素A微囊栓 ,考察其药动学性质。方法 :利用复凝聚法制备环孢素A微囊 ,并用于环孢素A微囊栓的研制 ;利用家兔进行药动学实验 ,用荧光偏振免疫分析仪测定血药浓度 ,以 3P97药动学软件按二室模型拟合 ,并对所得药动学参数进行统计学分析。结果 :环孢素A微囊栓的生物半衰期显著延长 (P <0 .0 5 ) ,AUC有增加的趋势。结论 :与环孢素A口服液和普通栓剂相比 ,环孢素A微囊栓具有一定缓释作用。     

1例少年肾移植患者环孢素的药动学分析及个体化给药

本文介绍1例少年肾移植患者术后按常规剂量口服环孢素A后血药浓度监测谷值偏低，根据患者的药代动力学参数及肝肾功能状态。应用微机软件制订个体给药方案，取得了满意的效果。     

环孢素A人体药动学影响因素分析

环孢素Ａ(ｃｙｃｌｏｓｐｏｒｉｎＡ ,ＣｓＡ)是一种高效免疫抑制剂 ,具有亲脂性的环状多肽结构 ,含 11个氨基酸。该药于 1971年从真菌Ｔｏｌｙｐｏｃｌａｄｉｕｍｉｎｆｌａｔｕｍ中分离出来 ,1978年首次用于临床 ,现广泛用于肾脏、肝脏、心脏、骨髓移植患者及自身免疫性疾病的治疗。ＣｓＡ可选择性地抑制Ｔ辅助淋巴细胞及免疫反应 ,主要作用于淋巴细胞增殖早期 ,抑制作用是可逆的。ＣｓＡ不抑制造血系统 ,也不直接作用于巨噬细胞 ,因而不引起白细胞和血小板减少。ＣｓＡ的主要不良反应为与剂量有关的肾毒性、肝毒性等。由于ＣｓＡ的生物利…     

环孢素A的药动学及其影响因素研究进展

目的:对不同人群环孢素A(CSA)的药动学及其主要影响因素进行综述,为临床实施CSA个体化用药方案提供参考。方法:以"Cyclosporine""Pharmacokinetic""Interaction""环孢素A""临床应用"等组合作为关键词,查阅1985-2014年Pub Med、中国医院知识总库等数据库中环孢素的药动学及相关影响因素的文献,并据此进行归纳和总结。结果:共查询到文献1 146条,其中有效文献31条。结果表明,不同年龄、种族、性别、遗传基因型和处于不同机体状态的人群,CSA在其体内的血药浓度、清除率(CL)等药动学参数存在显著差异。胆囊切除、肝硬化、肥胖手术等病理状态和细胞色素P45(0CYP)3A4酶抑制剂、P糖蛋白底物抑制剂联用时,均可升高CSA的血药浓度;促胃肠动力药、CYP3A4酶诱导剂、P糖蛋白底物诱导剂等联用时,可明显降低CSA的血药浓度。结论:CSA的药动学受多种因素影响。在未来的临床工作中,除了应加大CSA的血药浓度监测,还需开展相关基因型多态性的检测技术,以便及时调整CSA的给药剂量,促进临床个体化与合理用药。     

基于群体药动学的环孢素A个体化给药研究进展

环孢素A是一种钙调神经磷酸酶抑制剂,目前常用于预防移植后的免疫排斥反应以及治疗再生障碍性贫血、类风湿性关节炎、肾病综合征等疾病。因环孢素A治疗窗窄,体内药动学过程受多种因素影响,药动学个体差异大,在临床上需个体化用药。群体药动学采用非线性混合效应模型法建立药动学参数群体值模型,定量考察人口学特征、遗传因素及联合用药等对药动学参数的影响,在个体化用药中发挥着重要的作用。综述环孢素A的药动学特点及群体药动学相关研究进展,分析归纳影响环孢素A药动学过程的可能因素,为临床制定环孢素A个体化用药方案提供参考。     

合用盐酸黄连素前后环孢素A的人体药动学

目的 :研究健康受试者合用盐酸黄连素 (berberinehydrochloride ,Ber)前后环孢素A(cyclosporinA ,CsA)的动力学过程 ,以分析两药相互作用发生的部位。方法 :6名健康男性志愿者在单剂口服CsA 3mg·kg-1后开始连续服用Ber 30 0mg ,bid× 10d ,最后一次与单剂CsA 3mg·kg 　 -1同时口服。每次口服CsA后即按时采血 ,用FPIA法测定全血CsA浓度 ,并计算出药动学参数。结果 :在健康志愿者合用Ber后 ,CsA的AUC值增加 19.6 % ,差异具非常显著性 (P <0 .0 1)。结论 :推测Ber对CsA的影响部位可能主要在肠道 ,Ber可能增加CsA的吸收或减少肠代谢。     

Population pharmacokinetic study of cyclosporine in Chinese renal transplant recipients

Purpose  

To establish the population pharmacokinetic (PPK) model of cyclosporine (CsA) in Chinese renal transplant recipients and evaluate the influence of various indexes including CYP3A5 and MDR1 genetic polymorphism on pharmacokinetic parameters.     

环孢素对肾移植术后患者血脂影响的浓度依赖性(英文)

研究环孢素对血脂影响的浓度依赖性。方法对16例肾移植术后患者测定术前和术后血脂及环孢素血药浓度。结果在环孢素血药浓度与术后术前血浆胆固醇及甘油三酯差值之间无统计学相关性。但术后血浆胆固醇的增加在高浓度患者中具有统计学显著性(P>0.05)。结论环孢素对肾移植术后患者血脂的影响呈浓度依赖性。     

Atorvastatin does not affect the pharmacokinetics of cyclosporine in renal transplant recipients

Objective The aim of the present study was to evaluate the possible influence of atorvastatin on the pharmacokinetics of cyclosporine (INN ciclosporin) and its main metabolites, AM1 and AM9, in renal transplant recipients.Methods Whole blood samples from 18 renal transplanted patients on cyclosporine-based immunosuppressive therapy were collected prior to and after 4 weeks of treatment with atorvastatin (10 mg/day) and analysed with regard to both cyclosporine and its main metabolites, AM1 and AM9, using a specific chromatographic method with ultraviolet detection.Results On average, AUC_0-12 [area under the whole blood concentration versus time curve in the dosing interval (0–12 h)] of cyclosporine was 5% (–16, 5) (90% confidence interval) lower upon co-administration with atorvastatin. No statistically significant changes in any of the calculated pharmacokinetic variables [AUC_0-12, maximum whole blood concentration (C_max), whole blood concentration 12 h post dose (C₁₂), time to C_max (t_max), terminal half-life (t_1/2)] for cyclosporine or the two metabolites, AM1 and AM9, upon atorvastatin treatment were observed. On average, atorvastatin did not affect the ratio between the CYP3A4-mediated metabolite AM9 and cyclosporine, suggesting that atorvastatin does not affect the CYP3A4 metabolism of cyclosporine to any significant extent. However, the influence of atorvastatin on the ratio between AM9 and cyclosporine showed large interindividual variability.Conclusion The results of this study indicate that atorvastatin does not, on average, affect cyclosporine pharmacokinetics in renal transplant recipients.     

Pharmacokinetic interactions between microemulsion formulated cyclosporine A and diltiazem in renal transplant recipients

Objective: Bilateral cyclosporin A (CsA) and diltiazem pharmacokinetic interactions have previously been investigated, however, not with the new microemulsion preconcentrate formulation of CsA (Sandimmun Neoral). In addition, the pharmacokinetic effects on the pharmacological active metabolites of diltiazem have not previously been investigated. We performed a pharmacokinetic interaction study in renal transplant recipients, measuring both unmetabolised CsA and diltiazem in addition to three of the main metabolites of diltiazem (M_A, M₁, M₂). Methods: Nine CsA-treated renal transplant patients were treated with diltiazem, 90–120 mg b.i.d., for 4 weeks. Pharmacokinetic investigations were performed both before and at the end of the diltiazem treatment period. Six non-CsA-treated renal transplant patients served as controls of CsA interactions with diltiazem and its metabolites. Results: Diltiazem treatment resulted in a significant mean increase in the area under the concentration–time curve (AUC) for CsA of 51(8)% (P < 0.008) and a peak concentration (C_max) of 34(8)% (P < 0.05), without altering time to peak concentration (t _max). CsA, however, did not significantly influence diltiazem pharmacokinetics, though two of the metabolites (M₁ and M₂) tended to be increased. Conclusions: Diltiazem interacts significantly with the pharmacokinetics of CsA in the new microemulsion formulation. Microemulsion-formulated CsA, however, did not show significant interaction with diltiazem pharmacokinetics. Received: 21 September 1998 / Accepted in revised form: 18 February 1999     

Isoniazid does not affect bioavailability of cyclosporine in renal transplant recipients

Transplant recipients are predisposed to develop opportunistic infections such as tuberculosis, and isoniazid (INH) is used in most antitubercular therapeutic and prophylactic protocols. Cyclosporine (CyA) bioavailability increases with the concomitant use of drugs that inhibit hepatic cytochrome P-450 enzymes. There are conflicting reports on a possible interaction between the two drugs. Seven renal transplant recipients on CyA (Sandimmun Neoral) with slow acetylation status and also requiring concomitant INH prophylaxis (300 mg/day) against tuberculosis were studied. There were no significant changes in CyA pharmacokinetic parameters including CyA trough levels, total CyA exposure and CyA clearance before and 2 weeks after instituting INH prophylaxis. There was also no statistically significant correlation between INH levels and changes in CyA pharmacokinetic parameters before and after administration of INH. Even after all post-INH pharmacokinetic parameters were adjusted for INH levels, the differences in the above pre- and post-INH parameters did not reach statistical significance. Renal function during the study period remained constant and there were no episodes of CyA toxicity or acute rejection during and up to 4 weeks of INH treatment. We conclude that concomitant administration of INH and CyA is safe and is not associated with any appreciable alterations in the bioavailability of CyA.     

Pharmacokinetics of mycophenolic acid and metabolites in diabetic kidney transplant recipients

Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is an immunosuppressive agent commonly used after organ transplantation. Because diabetes mellitus may affect disposition of pharmacologic agents, we investigated the influence of diabetes on the pharmacokinetics of MPA, unbound MPA (fMPA) and its phenyl and acyl glucuronide metabolites (MPAG and AcMPAG respectively). The study included 13 diabetic and 11 nondiabetic, stable, kidney-transplant recipients who were receiving a triple maintenance immunosuppressive regimen. Serial plasma samples were obtained predose and at regular intervals for 12 hours. Gastric emptying was assessed using an acetaminophen absorption test and glomerular filtration rate was estimated using iohexol clearance. Treatment groups were well matched. The time to maximum concentration (Tmax) of MPA was 86.4 +/- 41.4 minutes versus 52.8 +/- 31.8 minutes in D and ND patients respectively (P = 0.04) indicating a delay in MMF absorption. Neither the maximum MPA concentration nor the 0- to 12-hour area under the concentration-time curve were different. All parameters derived for fMPA and the MPA metabolites were comparable between the 2 groups, except for the metabolite ratio of MPAG and AcMPAG, which was higher for diabetic patients (P = 0.03). Delayed gastric emptying seemed to have reduced the initial rate but not the extent of MPA absorption in diabetic patients. The profiles of fMPA were similar in both patient groups. With the exception of metabolite concentration ratio, none of the other parameters associated with MPA metabolism were different between the 2 groups.     

Pharmacokinetics and pharmacodynamic response of methylprednisolone in premenopausal renal transplant recipients

Chronic glucocorticoid therapy is prescribed in renal transplant recipients according to empiric dose-tapering schedules, which assume a similar pharmacologic response in men and women. The study objectives were (a) to compare the pharmacokinetics of methylprednisolone in premenopausal renal transplant recipients with previously studied male counterparts and (b) to describe the pharmacodynamic response of the hypothalamic-pituitary-adrenal axis during chronic steroid therapy. Thirteen stable premenopausal subjects (ages 30 to 相似文献   

Evaluation of the pharmacokinetic interaction between fluvastatin XL and cyclosporine in renal transplant recipients

OBJECTIVE: To assess the pharmacokinetic interaction between cyclosporine and extended-release fluvastatin (fluvastatin XL), 80 mg for 7 days, in stable renal transplant recipients. METHODS: This was a single-center, open-label study. 17 renal transplant recipients received their standard cyclosporine therapy (Days 1 - 9) plus a once-daily single oral dose of fluvastatin XL, 80 mg (Days 2 - 8). Blood samples were collected and cyclosporine (whole blood) and fluvastatin (plasma) concentrations determined by radioimmunoassay and HPLC fluorescence detection, respectively. Pharmacokinetic parameters were calculated using non-compartment analysis and fluvastatin results were compared with historical controls. RESULTS: Treatment with fluvastatin XL, 80 mg for 7 days, had no significant effect on either the AUC0-12 (3,644 ng x h/ml in the absence of fluvastatin vs. 3,534 ng x h/ml in the presence of fluvastatin) or the Cmax of cyclosporine (983 ng/ml in the absence of fluvastatin vs. 945 ng/ml in the presence of fluvastatin). Co-administration of fluvastatin XL also had no effect on the tmax, t1/2 or apparent clearance (CL/F) of cyclosporine in renal transplant patients. The AUC and Cmax for fluvastatin XL in the presence of cyclosporine (AUC0-24 1,192 ng. x h/ml, Cmax 271 ng/ml) were approximately 2-fold higher compared with historical data for fluvastatin XL alone in healthy volunteers (AUC0-24 630 ng x h/ml, Cmax 102 ng/ml) but lower than the historical data for fluvastatin IR, 40 mg b.i.d. alone in healthy volunteers (AUC0-24 1,340 ng x h/ml, Cmax 443 ng/ml). Tmax, t1/2 and trough levels of fluvastatin in the presence of cyclosporine were also similar to the historical controls. Concomitant administration of cyclosporine and fluvastatin XL was well tolerated by renal transplant recipients. CONCLUSIONS: Fluvastatin XL, 80 mg, and cyclosporine do not show clinically relevant pharmacokinetic interactions.     

回顾性研究细胞色素P4503A5基因多态性对肾移植病人环孢素浓度的影响

目的 回顾性研究稳定期肾移植的病人在合用地尔硫卓后,CYP3A5基因多态性对环孢素(免疫抑制剂)浓度的影响.方法 用RFLP-PCR检测CYP3A5基因型;采用回顾性研究方法,分析肾移植病人CYP3A5基因型与环孢素血药浓度的关系.结果 合用地尔硫卓的病人,按CYP3A5不同基因型分组,3组病人之间的环孢素剂量和剂量调整浓度有明显差异;而不用地尔硫卓的病人进行分组后,环孢素剂量调整浓度也存在显著差异;环孢素剂量调整浓度,CYP3A5表达者显著低于不表达者组.结论 CYP3A5基因型对稳定期肾移植病人环孢素药代动力学有显著影响,且此相关性不受合用地尔硫卓影响.     

PXR单核苷酸多态性与肾移植受者环孢素所致肝损伤的相关性研究

目的：探讨肾移植受者中PXR基因多态性与环孢素A （cyclosporine,CsA）血谷浓度和CsA致肝损伤易感性的相关性。方法：将入组的188例肾移植受者分为CsA致肝损伤组（16例）和对照组（172例）,采用多重PCR技术结合高通量二代测序技术对PXR基因的6个SNP位点（rs2276707 C>T、rs6784598 G>C、rs7643645 A>G、rs6771638 G>T、rs1523127 T>G、rs3814055 C>T）进行基因分型,采用TDx血药浓度分析仪检测CsA血谷浓度,分析PXR基因多态性对CsA血谷浓度的影响,同时比较PXR基因型及单倍型在CsA致肝损伤组与对照组间分布差异。结果：rs1523127（P^Dom=0.048 5）、rs3814055（P^Dom=0.048 5）、rs6784598（P^Dom=0.021 1、P^Add=0.036 6）术后36个月时间点血谷浓度C₀有显著性差异。rs6784598（P^Dom=0.049 2、P^Rec=0.011 7、P^Add=0.005 3）、rs7643645（P^Add=0.025 7、P^Dom=0.027 4）、rs2276707（P ^Dom=0.046 8）后12个月时间点间血谷浓度C₀有显著性差异;rs2276707（P^Add=0.049 1、P^Dom=0.023 9）术后7 d时间点有显著性差异。PXR基因各SNP位点的等位基因分布频率在CsA致肝损伤组与对照组间分布频率均无显著差异（P>0.05）。rs6771638位点的TG基因型在CsA致肝损伤组与对照组间的分布频率有显著差异（P=0.030）,TG+TT基因型在肝损伤组的分布频率更低,是CsA致肝损伤的保护性因素。PXR基因的单倍型与CsA所致肝损伤无明显相关性（P>0.05）。结论：PXR rs1523127、rs3814055、rs6784598、rs7643645、rs2276707与肾移植受者CsA血谷浓度显著相关;PXR rs6771638 G>T与CsA所致肝损伤相关,是CsA所致肝损伤的保护性因素。