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。     

Pharmacologic effects of calcium channel blockers on restenosis

The understanding and control of the healing process after percutaneous transluminal coronary angioplasty (PTCA) and of the pathogenesis of restenosis are incomplete. To date, only stent implantation has been shown to successfully reduce the rate of restenosis. Calcium channel blockers have positive effects on a number of processes that may be associated with restenosis, including reduction of platelet aggregation, minimization of vasospasm, and inhibition of mitogens. Clinical trials have therefore been performed to assess the effect of calcium channel blockers on restenosis and ischemia. A meta-analysis of five restenosis trials investigating calcium channel blockers demonstrated a 30% reduction in the risk for restenosis. The Coronary Angioplasty Amlodipine Restenosis Study (CAPARES) is therefore assessing the effect of amlodipine, a long-acting, third-generation calcium channel blocker in angioplasty patients. Therapy (amlodipine 5 mg with a forced titration to 10 mg once daily, or placebo), is begun 2 weeks before angioplasty and is continued for 4 months after the procedure. The rationale of CAPARES is that amlodipine may offer anti-ischemic protection before, during, and after angioplasty, may have more beneficial effects on restenosis and various clinical end points than calcium channel blockers used in previous trials, and may improve the long-term outcome of PTCA therapy.     

糖尿病肾移植患者环孢素A的药动学测定

目的:研究糖尿病肾移植患者环孢素A(CsA)的药动学。方法:32例肾移植患者(术前既有糖尿病史的16例)术后服用CsA达稳态后,于服药前、服药后1,2,3,4,6,8,12 h静脉取血,采用均相酶扩大免疫分析法(EMIT)测定CsA浓度,以BAPP3.0软件拟合药动学参数。结果:CsA在糖尿病肾移植患者中的消除半衰期(t1/2)和体内平均滞留时间(MRT)较非糖尿病肾移植患者显著性降低(P<0.01,P<0.05),达峰时间(tmax)显著延长(P<0.01)。达峰浓度(Cmax)分别为(1 556.7±656.9)mg.L-1和(1 409.6±478.7)mg.L-1(P<0.05),2组曲线下面积(AUC)差异无显著性。结论:糖尿病对肾移植患者术后CsA的吸收和消除过程具有一定的影响,但不影响其生物利用度。     

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.     

Direct effects of calcium channel blockers on duodenal calcium transport in vivo

The direct effects of verapamil, diltiazem and nifedipine on duodenal calcium transport were assessed in rats by the in vivo ligated loop technique, using luminal calcium concentrations at which active and passive transport mechanisms predominate (2 and 50 mM Ca, respectively). At 2 mM Ca, addition of verapamil (0.3-10 mM) to the luminal solution caused a concentration-dependent decrease in calcium lumen-to-plasma uptake and an increase in calcium plasma-to-lumen translocation, such that at 10 mM verapamil there was a net secretion of calcium into the duodenal lumen. In contrast, nifedipine (0.3-3 mM) was without effect on calcium transport, and diltiazem reduced calcium lumen-to-plasma uptake and net calcium absorption only at 10 mM, without influencing plasma-to-lumen translocation. The verapamil-induced increase in calcium plasma-to-lumen translocation was abolished by bile duct ligation. Calcium transport was unaffected by any calcium channel blocker at 50 mM luminal calcium. Thus, verapamil can directly influence active calcium translocation in the intestine, in vivo, and may affect calcium homeostasis during chronic oral treatment with this drug.     

钙通道阻滞剂对肾移植患者环孢素血药浓度/剂量的影响与CYP3A5基因多态性有关

目的:研究CYP3A5基因多态性对合用钙通道阻滞剂(CCBs)患者环孢素(CsA)血药浓度/剂量(C/D)的影响。方法:利用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)分析技术对69例肾移植患者CYP3A5基因进行分型,研究患者在合用CCBs后CsAC/D的差异及与CYP3A5基因型的关系。结果:CYP3A5基因型为*1/*1、*1/*3和*3/*3型的患者分别有8例、23例和38例。肾移植患者的CYP3A5A6986G多态性(CYP3A5*3)发生频率为71.74。未用CCBs的CYP3A5*1/*3和CYP3A5*3/*3患者其CsAC/D分别是野生型患者的1.73倍和2.43倍,CYP3A5*1/*1、*1/*3型患者在合用CCBs前后CsA的C/D明显提高(19.90±7.66vs36.01±8.18,34.33±7.87vs46.16±9.63ng.mL-1permg.kg-1;P<0.01,P<0.05),而CYP3A5*3/*3型患者CsA的C/D无明显变化(48.27±10.60vs46.42±9.24ng.mL-1permg.kg-1)。结论:CCBs对肾移植患者CsA的C/D的...     

Calcium channel blockers as the treatment of choice for hypertension in renal transplant recipients: fact or fiction

Posttransplantation hypertension has been identified as an independent risk factor for chronic allograft dysfunction and loss. Based on available morbidity and mortality data, posttransplantation hypertension must be identified and managed appropriately. During the past decade, calcium channel blockers have been recommended by some as the antihypertensive agents of choice in this population, because it was theorized that their vasodilatory effects would counteract the vasoconstrictive effects of the calcineurin inhibitors. With increasing data becoming available, reexamining the use of traditional antihypertensive agents, including diuretics and beta-blockers, or the newer agents, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers, may be beneficial. Transplant clinicians must choose antihypertensive agents that will provide their patients with maximum benefit, from both a renal and a cardiovascular perspective. Beta-blockers, diuretics, and ACE inhibitors have all demonstrated significant benefit on morbidity and mortality in patients with cardiovascular disease. Calcium channel blockers have been shown to possess the ability to counteract cyclosporine-induced nephrotoxicity. When compared with beta-blockers, diuretics, and ACE inhibitors, however, the relative risk of cardiovascular events is increased with calcium channel blockers. With the long-term benefits of calcium channel blockers on the kidney unknown and a negative cardiovascular profile, these agents are best reserved as adjunctive therapy to beta-blockers, diuretics, and ACE inhibitors.     

The polymorphism of the pharmacological effects of calcium channel blockers

In experiments on mice and rats it was shown that the studied calcium channel blockers--verapamil (finoptin, isoptin), nifedipine (corinfar), sensit (phendilin), cinnarizine (stugeron), diltiazem--are heterogeneous by their pharmacological properties. No relationships between the antiarrhythmic, anticonvulsant and cholinolytic effects of the compounds were revealed. It was supposed that the cholinolytic activity of nifedipine and diltiazem in arecoline salivation test reflects not their competitive relations with acetylcholine on the active surface of the receptor, but rather is realized at the level of the signal transmembrane transmission systems.     

The kinetics of cyclosporine and its metabolites in bone marrow transplant patients.

1. The pharmacokinetics of cyclosporine (CsA) and the time course of CsA metabolites were studied in five bone marrow transplant patients after intravenous (i.v.) administration on two separate occasions and once after oral CsA administration. 2. Cyclosporine and cyclosporine metabolites were measured in whole blood by h.p.l.c. 3. Cyclosporine clearance after i.v. administration decreased from 3.9 +/- 1.7 ml min-1 kg-1 to 2.0 +/- 0.6 ml min-1 kg-1 after 14 days of treatment. The mean +/- s.d. absolute oral bioavailability of cyclosporine was 17 +/- 11%. 4. Hydroxylated CsA (M-17) was the major metabolite in blood. There were no significant differences in the mean metabolite/CsA AUC ratios between the first and second i.v. studies. 5. After oral administration, the metabolite to CsA AUC ratios were higher for most metabolites compared to those observed in the second i.v. study, suggesting a contribution of intestinal metabolism to the clearance of CsA.     

N-型钙通道及其阻断剂研究进展

N-型电压依赖性钙通道主要分布于疼痛传递与调控通路的神经元突触末梢，参与疼痛介质（如谷氨酸和P物质）的释放和调节，在疼痛传递和调控过程中具有重要作用。因此，阻断N-型钙通道可以产生镇痛作用，特别是慢性疼痛和神经病理性疼痛。FDA已批准肽类阻断剂齐考诺肽鞘内给药，治疗全身性疼痛以及吗啡耐受或无效患者的严重慢性疼痛，证实N型钙通道是一个非常有意义的镇痛药物研究新靶标。近年来，口服有活性的小分子化合物研究越来越受到人们的重视，各种文献和专利报道的新结构类型层出不穷。本文就相关研究进行了综述。     

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.     

Analgesic effects of several calcium channel blockers in mice

The possibility that calcium channel blockers might produce antinociception and increase morphine analgesia was examined using the acetic acid writhing test in mice. Subcutaneous injections of diltiazem, verapamil, nicardipine, flunarizine and cinnarizine produced a dose-dependent antinociception. This activity of diltiazem was stereospecific; d-cis-diltiazem was more potent than 1-cis-diltiazem. All the calcium channel blockers studied increased morphine analgesia and displaced to the left the morphine dose-response curve. This effect of diltiazem was also stereospecific. These results suggest that calcium channel blockers can induce analgesia and increase morphine analgesia, possibly through a decrease in cellular calcium availability.     

Cutaneous effects of sirolimus in renal transplant recipients

Cancer is a major cause of death in immunosuppressed transplant patients. Therefore, sirolimus is frequently used in these patients for its immunosuppressive and antineoplastic properties. However, a variety of cutaneous side effects have resulted from sirolimus therapy. Consequently, dermatologists must be aware of such adverse events and understand the risks and benefits of discontinuing therapy.     

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     

羟苯磺酸钙在肾移植后蛋白尿治疗中的应用

目的探讨羟苯磺酸钙辅助治疗肾移植后蛋白尿的有效性和安全性。方法 60例肾移植后蛋白尿患者随机分为两组,每组30例,均常规应用免疫抑制剂治疗,观察组加用羟苯磺酸钙0.5 g,po,tid。分别于治疗前和治疗1、3、6个月后检测24 h尿蛋白定量(Urp)、尿N-乙酰-β-D-氨基葡萄糖苷酶(NAG)、血β2微球蛋白(β2-MG)、肌酐清除率(Ccr)、肝及肾功能,并记录不良反应的发生情况。结果治疗前两组各项指标均相近(P>0.05)。观察组临床总有效率、完全缓解率分别为83%、27%,均高于对照组(33%、7%,P<0.05),两组疗效差异显著(P<0.05)。对照组治疗后各项指标均无显著变化(P>0.05),观察组治疗1个月后,Urp、尿NAG酶、血β2-MG均开始下降,Ccr开始升高(P<0.05),且各观察时点Urp、尿NAG酶、血β2-MG低于对照组,Ccr高于对照组,差异均有显著意义(P<0.05)。治疗期间两组均未见严重不良反应。结论羟苯磺酸钙辅助治疗肾移植后蛋白尿安全有效。     

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.     

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。