BACKGROUND & AIMS: OBJECTIVE:To investigate whether FK506 (tacrolimus) can inhibit Fas- or A23187-induced interleukin (IL)-8 expression and cell death in A549 human alveolar epithelial cells, plus Fas-mediated acute lung injury in vivo. METHODS:Assays for IL-8, cell death, and caspase-3 activity were performed. A549 cells were treated with 25 micromol A23187 or 0.2 microg/ml agonistic anti-Fas antibody plus 5 ng/ml interferon-gamma (IFN-gamma). Tacrolimus was treated at 0.1-10 ng/ml. For in vivo experiment, agonistic anti-Fas antibody (Jo2) at 2.5 microg/g was intratracheally instilled into C57BL/6 mice. Neutrophils and protein contents in bronchoalveolar lavage (BAL) fluid were measured within 24 h of instillation. Mice were orally treated with 32 mg/kg of tacrolimus 24 h and 1 h prior to instillation. RESULTS:Both Fas and A23187 caused significant IL-8 expression and cell death in A549 cells. Tacrolimus inhibited A23187-induced IL-8 expression alone while it protected all Fas-mediated responses. Mice instilled intratracheally with Jo2 at 2.5 microg/g had significant increases in neutrophils, protein contents in BAL fluid and in expression of chemoattractants for neutrophils. These increases were reversed by tacrolimus. CONCLUSIONS:Tacrolimus serves as a therapeutic option for improving lung injury through inhibition of Fas-mediated inflammation.

背景与目标：

BACKGROUND & AIMS: :We report the case of a 43 year old male with no prior psychiatric history with apparent tacrolimus-induced psychosis. Previous reports have identified other neurotoxic adverse effects due to tacrolimus, however, to our knowledge, there are few reports that describe psychosis induced by the immunosuppressant drug. Although psychosis may be a rare adverse effect, it can have significant impact on the long-term prognosis and treatment in transplant recipients. It is imperative to quickly identify patients who develop a mental status change while on tacrolimus and to work with the appropriate transplant team in managing these patients. Treatment usually calls for prompt discontinuation of tacrolimus, substituting with another immunosuppressant, and possible use of antipsychotics.

背景与目标： : 我们报告了一名43岁的男性，没有既往的精神病史，患有明显的他克莫司引起的精神病。以前的报道已经确定了他克莫司引起的其他神经毒性不良反应，但是，据我们所知，很少有报道描述由免疫抑制剂引起的精神病。尽管精神病可能是一种罕见的不良反应，但它可能对移植受者的长期预后和治疗产生重大影响。必须快速识别在使用他克莫司时出现精神状态变化的患者，并与适当的移植团队合作管理这些患者。治疗通常需要立即停用他克莫司，用另一种免疫抑制剂替代，并可能使用抗精神病药。

BACKGROUND & AIMS: BACKGROUND:Treatment of adults with steroid-dependent minimal change nephrotic syndrome (SD-MCNS) can be a significant challenge. Cyclophosphamide (CYC) and cyclosporin (CYA) are often effective steroid-sparing agents. Tacrolimus (TAC) may be another treatment option. METHODS:This open, prospective cohort study enrolled Chinese adults with SD-MCNS. At the start of the study, we administered TAC or intravenous CYC together with prednisone (0.5 mg/kg/day), the dose of which was tapered off throughout the study. The TAC cohort received oral TAC (target trough blood level of 4-8 ng/ml) for 24 weeks and the CYC cohort received intravenous CYC (750 mg/m(2) body surface) once every 4 weeks for 24 weeks. RESULTS:Twenty-six patients met the criteria for enrollment (14 patients in the CYC group and 12 patients in the TAC group). One patient from each group discontinued treatment because of a drug-related side effect. Complete remission (CR) after the 24-week therapeutic period was 76.9% (10/13) in the CYC group and 90.9% (10/11) in the TAC group. The mean time required for CR in the TAC group was significantly less than in the CYC group (P = 0.031). Eight of 13 (61.5%) patients in the CYC group and 8 of 11 (72.7%) patients in the TAC group successfully stopped steroids and changed their status from steroid dependence. Sixty percent (6/10) of the CYC patients and 50% (5/10) of the TAC patients who achieved CR maintained remission during the follow-up period of 23.0 +/- 10.1 months. Four (40%) CYC patients and five (50%) TAC patients experienced relapses, and two CYC patients experienced frequent relapses. CONCLUSION:A 24-week course of TAC is a favorable steroid-sparing agent for treatment of Chinese adults with SD-MCNS. Therapy with TAC accompanied by a tapering dose of prednisolone appears to yield quicker remission than treatment with CYC together with prednisone.

背景与目标：

BACKGROUND & AIMS: :We encountered the rare case of a 50-year-old woman who developed rheumatoid arthritis (RA) while suffering from Takayasu's arteritis of arch vessel type. prednisolone (PSL) therapy was continued at a maintenance dose of 7.5 mg due to recurring inflammation. She was affected with RA for 7 years after Takayasu's arteritis. Disease-modifying antirheumatic drugs (DMARDs) were unusable because of side effects. In the summer of 2005, RA activity increased, and treatment with tacrolimus hydrate at 1.5 mg was started; thereafter, the activity of RA and Takayasu's arteritis was relieved, especially MRA findings. We report that therapy with tacrolimus hydrate markedly relieved two disorders, and review the literature.

背景与目标： : 我们遇到了一名50岁妇女的罕见病例，该妇女患有类风湿关节炎 (RA)，同时患有弓状血管类型的Takayasu动脉炎。由于炎症复发，泼尼松龙 (PSL) 治疗继续维持剂量为7.5 mg。Takayasu的动脉炎后，她患有RA已有7年之久。由于副作用，改善疾病的抗风湿药 (DMARDs) 无法使用。在夏季2005年，RA活性增加，并开始用他克莫司水合物1.5 mg治疗; 此后，RA和Takayasu动脉炎的活性得到缓解，尤其是MRA的发现。我们报告他克莫司水合物治疗可显着缓解两种疾病，并复习文献。

BACKGROUND & AIMS: :Tacrolimus is a first-line calcineurin inhibitor (CNI) and an integral part of the immunosuppressive strategy in solid organ transplantation. Being a dose-critical drug, tacrolimus has a narrow therapeutic index that necessitates periodic monitoring to maintain the drug's efficacy and reduce the consequences of overexposure. Tacrolimus is characterized by substantial intra- and inter-individual pharmacokinetic variability. At steady state, the tacrolimus blood concentration to daily dose ratio (C/D ratio) has been described as a surrogate for the estimation of the individual metabolism rate, where a low C/D ratio reflects a higher rate of metabolism. Fast tacrolimus metabolism (low C/D ratio) is associated with the risk of poor outcomes after transplantation, including reduced allograft function and survival, higher allograft rejection, CNI nephrotoxicity, a faster decline in kidney function, reduced death-censored graft survival (DCGS), post-transplant lymphoproliferative disorders, dyslipidemia, hypertension, and cardiovascular events. In this article, we discuss the potential role of the C/D ratio in a noninvasive monitoring strategy for identifying patients at risk for potential adverse events post-transplant.

背景与目标： 他克莫司是一线钙调神经磷酸酶抑制剂 (CNI)，是实体器官移植中免疫抑制策略的组成部分。他克莫司是一种剂量关键药物，其治疗指数很窄，需要定期监测以保持药物的疗效并减少过度暴露的后果。他克莫司的特征是个体内和个体间的药代动力学差异。在稳定状态下，他克莫司的血液浓度与日剂量比 (C/D比) 已被描述为估算个体代谢率的替代指标，其中低C/D比反映了较高的代谢率。快速他克莫司代谢 (低C/D比) 与移植后不良预后的风险相关，包括同种异体移植功能和存活率降低，同种异体移植排斥反应升高，CNI肾毒性，肾功能更快下降，死亡审查移植物存活率降低 (DCGS)，移植后淋巴增生性疾病，血脂异常，高血压和心血管事件。在本文中，我们讨论了C/D比率在无创监测策略中的潜在作用，以识别移植后潜在不良事件的风险患者。

BACKGROUND & AIMS: BACKGROUND:Adherence to immunosuppressive therapy, which is important to prevent rejection after organ transplantation, is influenced by satisfaction of patients with their medication regimen. OBJECTIVE:We investigated the effect of introducing a simplified medication regimen for renal transplant patients on treatment satisfaction, in particular, convenience. METHODS:In a prospective cohort study, treatment was switched from tacrolimus twice daily to tacrolimus once daily with a simultaneous change to a once-daily formulation of other drugs when applicable. Treatment satisfaction was measured in 75 participants with the validated Treatment Satisfaction Questionnaire for Medication version II. RESULTS:The treatment convenience score increased from a mean (SD) of 66.0 (14.5) to 78.5 (14.5) (P < 0.001). The mean (SD) daily number of medication ingestion time points diminished from 2.4 (0.7) to 1.6 (0.7) (P < 0.001), and the mean (SD) daily number of tablets decreased from 12.4 (3.3) to 9.1 (2.6) (P < 0.001). The self-reported adherence to the medication regimen increased from 79.7% to 94.6% (P < 0.001). CONCLUSIONS:The introduction of a simplified medication regimen enabled by the use of a once-daily formulation of tacrolimus increases treatment convenience after renal transplantation. This regimen had a beneficial effect on self-reported adherence.

背景与目标：

BACKGROUND & AIMS: :Cytochrome P450 3A4 (CYP3A4) is a major drug-metabolizing enzyme that is widely investigated. So far, no homozygous inactive variant has been described. We report on a 19-year-old kidney transplant patient suffering from Alport syndrome, who experienced unexpected high tacrolimus plasma trough levels during immunosuppressant therapy. Because nonadherence, liver failure, or drug-drug interactions could be excluded, we hypothesized a diminished metabolism of the drug caused by mutations in the main detoxification enzyme, CYP3A4. Exome sequencing revealed a novel single-nucleotide polymorphism (c.802C>T) resulting in a premature stop codon in CYP3A4 exon 5. Accordingly, no CYP3A4 protein could be detected in kidney biopsy tissue, and there was lack of expression in HepG2 cells transiently transfected with the mutated CYP3A4. In addition, the patient harbored inactive CYP3A5*3, resulting in loss of function of the entire CYP3A locus, explaining the deteriorated tacrolimus clearance. This is, to our knowledge, the first case of a complete failure of CYP3A4 in humans.

背景与目标： : 细胞色素P450 3A4 (CYP3A4) 是广泛研究的主要药物代谢酶。到目前为止，还没有描述纯合的无活性变体。我们报道了一名患有Alport综合征的19岁肾脏移植患者，他在免疫抑制剂治疗期间经历了意想不到的他克莫司血浆谷水平升高。由于不依从性，肝衰竭或药物相互作用可以排除，因此我们假设主要解毒酶CYP3A4突变导致药物代谢减少。外显子组测序揭示了一种新的单核苷酸多态性 (c.802C>T)，导致CYP3A4外显子5过早终止密码子。因此，在肾脏活检组织中未检测到CYP3A4蛋白，并且在突变的CYP3A4瞬时转染的HepG2细胞中缺乏表达。此外，患者携带无活性的CYP3A5 * 3，导致整个CYP3A基因座功能丧失，解释了他克莫司清除率恶化。据我们所知，这是CYP3A4在人类中完全失败的第一例。

BACKGROUND & AIMS: :Following organ engraftment, initial dosing of tacrolimus is based on recipient weight and adjusted by measured C(0) concentrations. The bioavailability and elimination of tacrolimus are affected by the patients CYP3A5 genotype. Prospective data of the clinical advantage of knowing patient's CYP3A5 genotype prior to transplantation are lacking. A nonparametric population model was developed for tacrolimus in renal transplant recipients. Data from 99 patients were used for model development and validation. A three-compartment model with first-order absorption and lag time from the dosing compartment described the data well. Clearances and volumes of distribution were allometrically scaled to body size. The final model included fat-free mass, body mass index, hematocrit, time after transplantation, and CYP3A5 genotype as covariates. The bias and imprecision were 0.35 and 1.38, respectively, in the external data set. Patients with functional CYP3A5 had 26% higher clearance and 37% lower bioavailability. Knowledge of CYP3A5 genotype provided an initial advantage, but only until 3-4 tacrolimus concentrations were known. After this, a model without CYP3A5 genotype predicted just as well. The present models seem applicable for clinical individual dose predictions but need a prospective evaluation.

背景与目标： : 器官植入后，他克莫司的初始剂量基于接受者的体重，并通过测量的C(0) 浓度进行调整。他克莫司的生物利用度和消除受患者CYP3A5基因型的影响。缺乏在移植前了解患者CYP3A5基因型的临床优势的前瞻性数据。针对肾移植受者的他克莫司建立了非参数种群模型。来自99名患者的数据用于模型开发和验证。具有一阶吸收和来自给药室的滞后时间的三室模型很好地描述了数据。间隙和分布量按体型大小进行了异同比例缩放。最终模型包括无脂肪质量，体重指数，血细胞比容，移植后时间和CYP3A5基因型作为协变量。在外部数据集中分别0.35和1.38偏差和不精确性。具有功能性CYP3A5的患者26% 更高的清除率和37% 更低的生物利用度。对CYP3A5基因型的了解提供了最初的优势，但直到已知3-4他克莫司浓度为止。此后，也可以预测没有CYP3A5基因型的模型。目前的模型似乎适用于临床个体剂量预测，但需要前瞻性评估。

BACKGROUND & AIMS: :Transformations of the macrocyclic lactone tacrolimus (1), an important immunosuppressive drug produced by Streptomyces species, are described. These transformation products are primarily of interest as reference substances for drug impurity analyses. Upon action of acid (p-toluenesulfonic acid in toluene), tacrolimus is dehydrated by loss of water from the β-hydroxyketone moiety with partial inversion of configuration at C-8, resulting in formation of 5-deoxy-Δ(5,6)-tacrolimus and 5-deoxy-Δ(5,6)-8-epitacrolimus. The structure of the latter was determined by single-crystal X-ray crystallography. The same products are formed upon action of free radicals (iodine in boiling toluene), along with formation of 8-epitacrolimus. The latter is converted by p-toluenesulfonic acid to 5-deoxy-Δ(5,6)-8-epitacrolimus. Treatment of tacrolimus with weak base (1,5-diazabicyclo[4.3.0]nonene) gives, in addition to 8-epitacrolimus, the open-chain acid corresponding to 5-deoxy-Δ(5,6)-tacrolimus, a rare non-cyclic derivative of tacrolimus. Strong base (t-butoxide) causes pronounced degradation of the molecule. Thermolysis of tacrolimus leads to ring expansion by an apparent [3,3]-sigmatropic rearrangement of the allylic ester moiety with subsequent loss of water from the β-hydroxyketone moiety. ¹H and ¹³C NMR spectra of the obtained compounds, complicated by the presence of amide bond rotamers and ketal moiety tautomers, were assigned by extensive use of 2D NMR techniques.

背景与目标： : 描述了由链霉菌种产生的重要免疫抑制药物大环内酯他克莫司 (1) 的转化。这些转化产物主要是作为药物杂质分析的参考物质。在酸 (对甲苯磺酸在甲苯中的作用) 的作用下，他克莫司通过从 β-羟基酮部分失水而脱水，并在C-8处部分反转构型，导致形成5-脱氧-Δ(5,6)-他克莫司和5-脱氧-Δ(5,6)-8-表阿莫司。后者的结构是通过单晶x射线晶体学确定的。在自由基 (沸腾的甲苯中的碘) 的作用下，形成了相同的产物，并形成了8-依地莫司。后者被对甲苯磺酸转化为5-脱氧-Δ(5,6)-8-依他克莫司。用弱碱 (1,5-二氮杂双环 [4.3.0] 壬烯) 处理他克莫司，除了8-表位莫司外，还得到与5-脱氧-Δ(5,6)-他克莫司相对应的开链酸，他克莫司的一种罕见的非环衍生物。强碱 (叔丁醇) 导致分子明显降解。他克莫司的热解通过烯丙基酯部分的明显的 [3,3]-sigmatropic重排导致环膨胀，随后从 β-羟基酮部分失去水。通过广泛使用2D NMR技术，分配了获得的化合物的h和c NMR光谱，其中酰胺键旋转异构体和缩酮部分互变异构体的存在。

BACKGROUND & AIMS: :The cutaneous manifestations of autoimmune diseases, including systemic lupus erythematosus, are common and often recalcitrant to treatment. Unfortunately, therapy for lupus and other autoimmune skin diseases has not advanced and relies heavily on the use of oral and topical corticosteroids. Frequently, treatments prove less than ideal, either from toxicity or lack of efficacy. A topical form of the immunomodulating transplant medication, tacrolimus (FK-506, Protopic), has recently been developed and approved for use in treating atopic dermatitis. Its mechanism of action and local route of administration render tacrolimus a potentially attractive novel therapeutic alternative for the treatment of various autoimmune dermatologic conditions. We report our successful experience using this drug in 3 patients with autoimmune dermatologic disease who were referred to a tertiary care subspecialty clinic.

背景与目标： : 自身免疫性疾病 (包括系统性红斑狼疮) 的皮肤表现是常见的，并且经常难以治疗。不幸的是，狼疮和其他自身免疫性皮肤病的治疗尚未进展，严重依赖于口服和局部皮质类固醇的使用。通常，无论是毒性还是缺乏疗效，治疗都不理想。最近开发了一种局部形式的免疫调节移植药物他克莫司 (FK-506，Protopic)，并批准用于治疗特应性皮炎。他克莫司的作用机制和局部给药途径使他克莫司成为治疗各种自身免疫性皮肤病的潜在有吸引力的新型治疗选择。我们报告了我们在3例自身免疫性皮肤病患者中使用这种药物的成功经验，这些患者被转诊到三级护理亚专科诊所。

BACKGROUND & AIMS: BACKGROUND:Recent studies in murine models of allergic contact dermatitis have shown that systemic treatment with pimecrolimus in contrast to tacrolimus did not inhibit the sensitization phase, whereas both compounds equivalently suppressed the inflammatory response in sensitized animals. This finding indicated a differential sensitivity of antigen-naïve and primed T cells towards pimecrolimus and tacrolimus. METHODS:T cells obtained from healthy and allergic donors were subjected to primary and secondary stimulation by allogeneic or staphylococcal superantigen-presenting dendritic cells (DC). Human skin-derived, allergen-specific T cell clones from an atopic dermatitis patient were activated by anti-CD3 antibodies or by specific allergen-presenting DC. The inhibition of T cell proliferation and cytokine release by graded doses of calcineurin inhibitors was evaluated. RESULTS:Primary stimulation of T cells was inhibited by pimecrolimus with an approximately 8-fold lower potency as compared with tacrolimus. In contrast, the secondary response of ex vivo expanded T cells activated by allogeneic or staphylococcal superantigen-presenting DC was inhibited by both compounds with equivalent potency. Likewise, both drugs showed very similar potency to inhibit the proliferation and cytokine synthesis from antigen- stimulated T cell clones and the induction of cytokines in Jurkat T cells. CONCLUSION:These data indicate that pimecrolimus has a selectivity for antigen-primed memory T cells not seen with tacrolimus.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:Corticosteroids have long been a cornerstone of orthotopic liver transplant (OLTx) immunosuppression. Newer, more potent, agents have successfully allowed for more rapid tapering and discontinuation of corticosteroids in OLTx recipients. We hypothesize that corticosteroids can be safely avoided after the first postoperative day (POD) using these newer agents.

METHODS:Thirty adult OLTx recipients were prospectively enrolled in a randomized open-label, institutional review board-approved protocol. Fifteen patients (group A) received our standard regimen of tacrolimus, mycophenolate mofetil, and corticosteroids, and 15 patients (group B) received daclizumab, 2 mg/kg on POD 0 and 14, with tacrolimus, mycophenolate mofetil, and corticosteroids on POD 0 and 1 and then discontinuation. In both groups, mycophenolate mofetil was tapered off between 3 and 4 months after OLTx. Bone mineral densitometry was performed at 1, 3, and 6 months after OLTx. Quantitative hepatitis C virus (HCV) polymerase chain reaction was obtained at days 0, 7, 14, 21, and 28. Retransplant recipients, patients with autoimmune hepatitis, or status 1 or 2A patients were excluded.

RESULTS:Patient and graft survival rates were 93% (group A) and 100% (group B) with mean follow-up of 18 months. Patients in group B had more rejection diagnosed (25%) compared with group A (6.7%). Yet, the incidence of biopsy-proven acute rejection requiring steroid therapy was 6.7% in both groups. Hispanic race was common in groups A and B (87% and 74%). A total of six biopsies were performed in group B, with three patients having mild rejection responding to an increase in tacrolimus without the need for corticosteroids. One patient in group B was switched to cyclosporine for severe neurotoxicity and remains on monotherapy with normal graft function. No patient in either group developed a requirement for additional antihypertensive medication. Likewise, there were no patients with new-onset diabetes. The bone mineral densitometry was higher in group B at every time point but did not reach statistical significance. Serum cholesterol level was significantly (P=0.03) lower in group B at 6 months after OLTx. Serum triglycerides were also lower, but the difference was not significant. Quantitative polymerase chain reaction for HCV-positive patients (group A, n=7; group B, n=8) frequently increased after OLTx. There was no correlative decrease associated with daclizumab. At present, two patients in group A have documented HCV recurrence.

CONCLUSION:Corticosteroids can be safely avoided after POD 1 with the current regimen. With early follow-up, there is no difference in hypertension or diabetes or bone density. Lipid panels tended to be lower in patients who were not on corticosteroids. Longer term follow-up will be needed to demonstrate the potential advantage of corticosteroid avoidance in regard to hypertension, diabetes, and possibly HCV recurrence.

背景与目标： 背景 : 皮质类固醇长期以来一直是原位肝移植 (OLTx) 免疫抑制的基石。更新，更有效的药物已成功地使OLTx接受者的皮质类固醇激素更快速地逐渐减少和停用。我们假设使用这些新型药物可以在术后第一天 (POD) 安全避免使用皮质类固醇。
方法 : 30名成年OLTx接受者被前瞻性纳入了随机开放标签，机构审查委员会批准的方案。15例患者 (A组) 接受了他克莫司，霉酚酸酯和皮质类固醇的标准方案，15例患者 (B组) 在POD 0和14上接受了2 mg/kg的达珠单抗，在POD 0和1上接受他克莫司，霉酚酸酯和皮质类固醇，然后停用。在两组中，霉酚酸酯在OLTx后3至4个月之间逐渐减少。在OLTx后1、3和6个月进行骨矿物质密度测定。在第0、7、14、21和28天获得了定量的丙型肝炎病毒 (HCV) 聚合酶链反应。排除了再移植受者，自身免疫性肝炎患者或状态1或2A患者。
结果 : 患者和移植物存活率分别为93% (A组) 和100% (B组)，平均随访18个月。与A组 (25%) 相比，B组患者的排斥反应更多 (6.7%)。然而，在两组中，经活检证实的需要类固醇治疗的急性排斥反应的发生率均6.7%。西班牙裔种族在A组和B组 (87% 和74%) 中很常见。B组共进行了6次活检，其中3例患者对他克莫司的增加有轻度排斥反应，而无需使用皮质类固醇。B组的一名患者因严重的神经毒性而改用环孢素，并继续接受移植功能正常的单药治疗。两组都没有患者需要额外的抗高血压药物。同样，也没有新发糖尿病患者。B组的骨矿物质密度在每个时间点均较高，但未达到统计学意义。在OLTx后6个月，B组的血清胆固醇水平显着降低 (P = 0.03)。血清甘油三酯也较低，但差异不显著。HCV阳性患者 (A组，n = 7; B组，n = 8) 的定量聚合酶链反应在OLTx后频繁增加。没有与达珠单抗相关的减少。目前，A组中有两名患者已记录了HCV复发。
结论 : 使用当前方案的POD 1后，可以安全地避免皮质类固醇。随着早期随访，高血压，糖尿病或骨密度没有差异。未使用皮质类固醇的患者的脂质组趋于降低。需要进行长期随访，以证明避免使用皮质类固醇激素在高血压，糖尿病和可能的HCV复发方面的潜在优势。

BACKGROUND & AIMS: The effects of renal failure on the hepatic and intestinal extraction of tacrolimus were evaluated to examine the mechanisms for the increased bioavailability of this drug in cisplatin-induced renal failure model rats. Tacrolimus extractions in the liver and intestine were evaluated by intravenous, intraportal and intraintestinal infusion. The intestinal metabolism and absorption rate were estimated by incubating the isolated intestine with drug solution and by an in situ loop method, respectively. Blood concentrations of tacrolimus following the intraintestinal infusion were significantly increased in rats with renal failure compared with those in normal rats. The blood concentration of tacrolimus during intraportal infusion in rats with renal failure showed non-linearity against dose, and was increased as compared with that in normal rats. The intestinal metabolism was not altered, but the absorption rate was significantly increased in the intestine from rats with renal dysfunction. These results suggest that the hepatic metabolism of tacrolimus is impaired in rats with renal failure, and that the accelerated absorption rate in the intestine in renal dysfunction is followed by partial saturation of hepatic extraction, which may be one of the mechanisms of increased bioavailability of tacrolimus.

背景与目标： 评估了肾衰竭对他克莫司肝和肠提取的影响，以研究该药物在顺铂诱导的肾衰竭模型大鼠中生物利用度增加的机制。通过静脉内，静脉内和肠内输注评估他克莫司在肝脏和肠道中的提取液。分别通过将分离的肠与药物溶液一起孵育和通过原位循环方法来估算肠的代谢和吸收率。与正常大鼠相比，肾衰竭大鼠在肠内输注后他克莫司的血药浓度显着增加。肾衰竭大鼠在静脉内输注过程中他克莫司的血药浓度显示出对剂量的非线性，并且与正常大鼠相比有所增加。肠道代谢没有改变，但肾功能不全大鼠的肠道吸收率显着增加。这些结果表明，他克莫司的肝代谢在肾功能衰竭大鼠中受损，肾功能不全时肠道吸收速度加快，肝提取部分饱和，这可能是他克莫司生物利用度增加的机制之一。

BACKGROUND & AIMS: BACKGROUND:Wide variation in tacrolimus concentrations and low tacrolimus exposure have been reported to be associated with poor renal graft outcomes in non-Asians. The CYP3A5 polymorphism is a representative genetic factor that might affect this association, together with environmental factors. We investigated whether tacrolimus variability or the mean tacrolimus trough concentration can influence kidney allograft outcomes in Asians and whether the CYP3A5 polymorphism (rs776746) can affect this relationship. METHODS:Data from renal transplant patients between 2000 and 2010 were analyzed retrospectively. The tacrolimus intraindividual variability (IIV) and the mean tacrolimus trough concentration were calculated from the tacrolimus concentrations between 6 and 12 months after transplantation. RESULTS:A total of 249 renal transplant patients were enrolled. The patients with higher tacrolimus IIV had shorter rejection-free survival (P = 0.002). However, there was no difference in rejection-free survival between CYP3A5 expressers and nonexpressers. The tacrolimus IIV was not associated with the CYP3A5 polymorphism. High IIV of tacrolimus was an independent risk factor of biopsy-proven acute rejection after adjusting for mean tacrolimus concentration, HLA mismatch, induction therapy, donor type, and CYP3A5 polymorphism (hazard ratio 2.655, 95% confidence interval 1.394-5.056). Interestingly, the impact of tacrolimus IIV on acute rejection was significant in CYP3A5 expressers, whereas it was not in CYP3A5 nonexpressers. CONCLUSIONS:The IIV of tacrolimus trough concentrations had a significant impact on rejection-free survival. The effect was influenced by CYP3A5 polymorphism, although the tacrolimus variability itself was not determined by the CYP3A5 polymorphism.

背景与目标：

BACKGROUND & AIMS: :Autoimmune hemolytic anemia (AIHA) has been reported to occur after renal transplantation, and typically does so in the first few weeks post-transplant. We report on a 3-yr-old child who developed cold AIHA nearly 1 yr after an ABO identical, living donor renal transplant from his mother. Numerous transfusions, pulse steroids, repeat plasma exchange treatments, and IVIG were unsuccessful. Nearly 3 wk into his illness, tacrolimus was changed to cyclosporine, and then to sirolimus, and resulted in a prompt response. He currently has a normal renal function and a normal hemoglobin level on sirolimus monotherapy.

背景与目标： : 据报道，肾移植后发生自身免疫性溶血性贫血 (AIHA)，通常在移植后的最初几周内发生。我们报告了一个3岁的孩子，该孩子在母亲进行ABO相同的活体供体肾移植后近1年出现了冷AIHA。大量输血，脉冲类固醇，重复血浆交换治疗和IVIG均未成功。近3周，他克莫司被改为环孢素，然后改为西罗莫司，并导致迅速反应。他目前在西罗莫司单药治疗中肾功能正常，血红蛋白水平正常。