Reports have been conflicting as to whether low tacrolimus trough concentrations are related to rejection. Several studies have demonstrated a correlation between high trough concentrations and toxicity, particularly nephrotoxicity. The best predictor of pharmacological effect may be drug concentrations in the transplanted organ itself. Researchers have started to question current reliance on trough measurement during therapeutic drug monitoring, with instances of toxicity and rejection occurring when trough concentrations are within 鈥榓cceptable鈥 ranges. The correlation between blood concentration and drug exposure can be improved by use of non-trough timepoints. However, controversy exists as to whether this will provide any great benefit, given the added complexity in monitoring. Investigators are now attempting to quantify the pharmacological effects of tacrolimus on immune cells through assays that measure in vivo calcineurin inhibition and markers of immunosuppression such as cytokine concentration. To date, no studies have correlated pharmacodynamic marker assay results with immunosuppressive efficacy, as determined by allograft outcome, or investigated the relationship between calcineurin inhibition and drug adverse effects. Little is known about the magnitude of the pharmacodynamic variability of tacrolimus.

The calcineurin inhibitor tacrolimus is the backbone of immunosuppressive drug therapy after solid organ transplantation. Tacrolimus is effective in preventing acute rejection but has considerable toxicity and displays marked inter-individual variability in its pharmacokinetics and pharmacodynamics. The genetic basis of these phenomena is reviewed here. With regard to its pharmacokinetic variability, a single nucleotide polymorphism (SNP) in cytochrome P450 (CYP) 3A5 (6986A > G) has been consistently associated with tacrolimus dose requirement. Patients expressing CYP3A5 (those carrying the A nucleotide, defined as the *1 allele) have a dose requirement that is around 50 % higher than non-expressers (those homozygous for the G nucleotide, defined as the *3 allele). A randomised controlled study in kidney transplant recipients has demonstrated that a CYP3A5 genotype-based approach to tacrolimus dosing leads to more patients reaching the target concentration early after transplantation. However, no improvement of clinical outcomes (rejection incidence, toxicity) was observed, which may have been the result of the design of this particular study. In addition to CYP3A5 genotype, other genetic variants may also contribute to the variability in tacrolimus pharmacokinetics. Among these, the CYP3A4*22 and POR*28 SNPs are the most promising. Individuals carrying the CYP3A4*22 T-variant allele have a lower tacrolimus dose requirement than individuals with the CYP3A4*22 CC genotype and this effect appears to be independent of CYP3A5 genotype status. Individuals carrying the POR*28 T-variant allele have a higher tacrolimus dose requirement than POR*28 CC homozygotes but this association was only found in CYP3A5-expressing individuals. Other, less well-defined SNPs have been inconsistently associated with tacrolimus dose requirement. It is envisaged that in the future, algorithms incorporating clinical, demographic and genetic variables will be developed that will aid clinicians with the determination of the tacrolimus starting dose for an individual transplant recipient. Such an approach may limit early tacrolimus under-exposure and toxicity. With regard to tacrolimus pharmacodynamics, no strong genotype-phenotype relationships have been identified. Certain SNPs associate with rejection risk but these observations await replication. Likewise, the genetic basis of tacrolimus-induced toxicity remains unclarified. SNPs in the genes encoding for the drug transporter ABCB1 and the CYP3A enzymes may relate to chronic nephrotoxicity but findings have been inconsistent. No genetic markers reliably predict new-onset diabetes mellitus after transplantation, hypertension or neurotoxicity. The CYP3A5*1 SNP is currently the most promising biomarker for tailoring tacrolimus treatment. However, before CYP3A5 genotyping is incorporated into the routine clinical care of transplant recipients, prospective clinical trials are needed to determine whether such a strategy improves patient outcomes. The role of pharmacogenetics in tacrolimus pharmacodynamics should be explored further by the study of intra-lymphocyte and tissue tacrolimus concentrations.

Background. Goal tacrolimus concentrations for the prevention of rejection in sensitized renal transplant recipients are not well established.<br/>Methods. We evaluated the association between discharge tacrolimus trough concentration and the incidence of biopsy-proven acute rejection (BPAR) in 216 moderately sensitized renal transplant recipients (negative flow crossmatch and positive donor-specific antibodies) treated with tacrolimus.<br/>Results. At transplant, the mean +/- standard deviation (SD) peak panel-reactive antibody was 60 +/- 33 and median donor-specific antibody level was a mean fluorescence intensity of 710 (interquartile range, 328-1202). The mean +/- SD tacrolimus trough concentration at discharge (median postoperative day, 5; interquartile range, 4-7) was 7.6 +/- 3.7 ng/dL. Patients were divided into two groups based on a discharge tacrolimus trough concentration of 8 ng/mL. Baseline characteristics were similar between groups. Thirty-four (28.6%) of the 119 patients with a tacrolimus trough concentration less than 8 ng/mL and 19 (19.6%) of 97 patients with concentrations of 8 ng/mL or greater experienced BPAR during a median follow-up of 14 +/- 4.7 months (P=0.04). Adjusting for age, race, donor status, and peak panel-reactive antibody, a discharge tacrolimus trough concentration less than 8 ng/mL was significantly associated with a higher risk of BPAR (hazard ratio, 1.84; 95% confidence interval, 1.04-3.25; P=0.04). Serum creatinine, cytomegalovirus, BKviremia, or BK nephropathy at 1 year did not differ between groups.<br/>Conclusions. In a patient population predisposed to BPAR, discharge tacrolimus trough concentration less than 8 ng/mL was associated with a nearly two times greater risk of BPAR.

<P>本文报道了过氧化氢诱发原代培养大鼠肝细胞毒性作用的可能机理. 过氧化氢（0.2～1.0 mmol·L<SUP>-1</SUP>) 温育6 h可以引起大鼠肝细胞坏死性损伤，导致谷丙转氨酶释放增加及细胞存活率下降，加入过氧化氢酶（250 ～1500 U·mL<SUP>-1</SUP>) 及抗氧化剂五味子乙素 (10～100 μmol·L<SUP>-1</SUP>) 均可降低过氧化氢的毒性作用. 加入过氧化氢 (0.6和1.0 mmol·L<SUP>-1</SUP>) 可在6 min内使大鼠肝细胞内钙从180 nmol·L<SUP>-1</SUP>明显持续升高至700 nmol·L<SUP>-1</SUP>以上（约3.5倍). 过氧化氢与肝细胞作用30 min至1 h既可导致细胞膜脂质过氧化，表现为丙二醛蓄积及膜流动性下降，明显早于肝细胞发生坏死性损伤的时间. 肝细胞胞浆中还原型谷胱甘肽(GSH)含量在加入过氧化氢30 min后明显降低，可推测肝细胞在后面的温育中对过氧化氢毒性的敏感性增加. 以上结果证实过氧化氢诱发的原代培养大鼠肝细胞致死性损伤可能与细胞内钙迅速持续增高，细胞膜脂质过氧化及GSH含量下降有关.</P>

目的观察五脂胶囊对病毒性肝炎和脂肪肝引起肝功能异常的治疗疗效。方法选择感染科门诊病毒性肝炎及脂肪肝患者共109例，比较服用五脂胶囊前后的谷丙转氨酶（ALT）、谷草转氨酶（AST）、r-谷氨酰转肽酶（GGT）等生化指标的变化。结果服用五脂胶囊后ALT、AST、GGT等生化指标均明显降低，与用药前比较均有显著性差异（P〈0．05），五脂胶囊对病毒性肝炎的疗效高于脂肪肝（P〈0．05），对病毒性肝炎组的ALT及对脂肪肝组的AST降酶作用较强。结论五脂胶囊对病毒性肝炎、脂肪肝两种肝病患者具有强的降酶作用。

目的:研究健康受试者合用中药制剂五酯胶囊(Wuzhi-capsule,WZ)前后他克莫司 (tacrolimus,Tac)的动力学过程,观察两药是否存在相互作用.方法:研究分两期,12例健康男性志愿者在第一周期单剂口服Tac 2 mg后,开始连续服用五酯胶囊3粒,bid,连服13 d;在第二周期再单剂口服Tac 2 mg,同时服用五酯胶囊3粒.每期口服Tac后即按设计的时间采血,用ELISA法测定全血Tac浓度,并计算药动学参数.结果:合用五酯胶囊前后Tac 的主要药动学参数:AUC0～24 h分别为(129.48±68.90)和(274.82±64.93)μg·L-1·h;t1/2分别为(9.39±3.13)和 (8.11±3.56)h;CL(s)分别为(17.72±17.30)和(6.55±1.55)L·h-1;Tmax分别为(1.42±0.36)和 (1.83±0.25)h;Cmax分别为(22.21±10.61)和(66.44±21.27)μg·L-1;V/F(C)分别为 (179.94±41.27)和(72.81±28.07)L.与合用五酯胶囊前相比,Tac的AUC0～24 h和Cmax分别增加164.2%和227.1%,CL(s)降低49.0%,Tmax显著延迟.结论:五酯胶囊能显著增加Tac的血浓度和生物利用度.

AIM: To assess the effect of extract (SchE) on the pharmacokinetics of tacrolimus in healthy volunteers.: Twelve healthy male volunteers were orally treated with SchE, three twice daily for 13 days. Pharmacokinetic investigations of oral tacrolimus administration at 2 mg were performed both before and at the end of the SchE treatment period. Whole blood tacrolimus concentrations were determined by enzyme-linked immunosorbent assay. Estimated pharmacokinetic parameters before and with SchE were calculated with noncompartmental techniques.: Following administration of SchE, the average percentage increases of individual increases in AUC, AUMC and C(max) of tacrolimus were 164.2% [95% confidence interval (CI) 70.1, 258.4], 133.1% (95% CI 49.5, 261.3) and 227.1% (95% CI 155.8, 298.4), respectively (P < 0.01 or 0.05). On average, there was a 36.8% (95% CI 13.4, 60.2) increase in tacrolimus t(max) (P < 0.01). The average percentage decreases in CL/F and V/F were 49.0% (95% CI 31.1, 66.9) and 53.7% (95% CI 40.1, 67.4), respectively (P < 0.01).: SchE can increase the oral bioavailability of tacrolimus. The results of this study will add important information to the interaction area between drugs and herbal products.

目的:研究五酯胶囊(Wuzhi-capsule,WZ)与他克莫司(Tacrolimus,Tac)联 合应用对肾移植受者Tac血浓度的影响.方法:45名服用Tac+WZ患者为试验组,45名单服Tac患者为对照组,以Tac全血浓度及肝、肾功能生化检 测指标作为临床评价指标.结果:合用WZ患者Tac全血浓度与合用前比较明显增加(P＜0.01),与对照组比较亦有显著性提高(P＜0.01).WZ与 Tac合用对肝、肾功能无明显影响.结论:WZ能明显升高肾移植受者Tac血浓度.在升高Tac血浓度的同时,WZ并不增加Tac的肝肾毒性反应.WZ与 Tac合用可减少Tac用药量,节省Tac费用.

目的:研究五酯胶囊(Wuzhi-capsule,WZ)与他克莫司(Tacrolimus,Tac)联 合应用对肾移植受者Tac血浓度的影响.方法:45名服用Tac+WZ患者为试验组,45名单服Tac患者为对照组,以Tac全血浓度及肝、肾功能生化检 测指标作为临床评价指标.结果:合用WZ患者Tac全血浓度与合用前比较明显增加(P＜0.01),与对照组比较亦有显著性提高(P＜0.01).WZ与 Tac合用对肝、肾功能无明显影响.结论:WZ能明显升高肾移植受者Tac血浓度.在升高Tac血浓度的同时,WZ并不增加Tac的肝肾毒性反应.WZ与 Tac合用可减少Tac用药量,节省Tac费用.

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.

目的 评价五酯胶囊对肝移植受者术后服用他克莫司血药浓度的影响.方法 选取60例肝移植受者,随机分成2组,试验组32例,口服他克莫司的同时,加服五酯胶囊；对照组28例,服用他克莫司,未服五酯胶囊,连续服药6个月,比较2组他克莫司的用量、血药浓度及肝肾功能生化指标.结果 服用五酯胶囊后,试验组他克莫司血药浓度升高,相应减少服用量,试验组每日服用他克莫司剂量比对照组显著降低(P＜0.01)；但术后1,2,3,4,6月复查,2组他克莫司血药浓度及肾功能(Cr)无明显差异(P＞0.05)；试验组与对照组比较,肝功能(ALT)有所改善,差异有统计学意义(P＜0.05).结论 五酯胶囊能明显提高肝移植受者他克莫司全血浓度,同时减少他克莫司服用量,降低患者医疗费用.

目的 探讨五酯胶囊对肝移植术后服用FK506患者的血药浓度的影响.方法 选取57例肝移植术后口服他克莫司(Tacrolimus,FK506)的患者,加服五酯胶囊,监测FK506血药浓度.结果 一周后FK506全血谷值浓度显著升高(P＜0.01),每日服用FK506剂量及临床费用显著降低(P＜0.01);随访期间急性排斥反应发生率没有增 加,肝肾功能保持稳定.结论 在保证免疫抑制效果的同时,五酯胶囊可以作为增效剂提高FK506的血药浓度并保持稳定,降低用量.

Since the first heart transplantation (HT) in 1967, survival has steadily improved. Issues related to over- and under-immunosuppression are, however, still common following HT. Whereas under-immunosuppression may result in rejection, over-immunosuppression may render other medical problems, including infections, malignancies and chronic kidney disease (CKD). As such complications constitute major limiting factors for long-term survival following HT, identifying improved diagnostic and preventive methods has been the focus of many studies. Notably, research on antibody-mediated rejection (AMR) and cardiac allograft vasculopathy (CAV) has recently led to the development of nomenclatures that may aid in their diagnosis and treatment. Moreover, novel immunosuppressants (such as mammalian target of rapamycin [m-TOR] inhibitors) and strategies aimed at minimizing the use of calcineurin inhibitors (CNIs) and corticosteroids (CSs), have provided alternatives to the traditional combination maintenance immunosuppressive therapy of CSs, cyclosporine (CSA) or tacrolimus (TAC), and azathioprine (AZA) or mycophenolate mofetil (MMF). Research within this field of medicine is not only extensive, but also in constant progress. The purpose of the present review was therefore to summarize some major points regarding immunosuppressive therapies after HT and the balance between under- and over-immunosuppression. Transplant immunology, rejection, common medical problems related to over-immunosuppression, as well as induction and maintenance immunosuppressive drugs and therapies, are addressed. Copyright 漏 2015. Published by Elsevier Inc.

Abstract Background: Although survival among heart recipients has increased, a limiting factor is chronic adverse effects of immunosuppression therapy. Material and methods: We performed a retrospective analysis of 22 patients (19 men and 3 women) with a mean age of 48 ± 12 years who underwent orthotropic heart transplantation. There were 20 (91%) patients who received induction therapy (basiliximab, Simulect, Novartis Europharm Limited). All patients were treated with standard triple immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and steroids). Results: Patients were divided into 2 groups according to postoperative peripheral cytopenia diagnosis. There were 16 (73%) in the cytopenic group and 6 (27%) in the non-cytopenic group. Mean time of peripheral leucopenia detection was 65 ± 13 days following surgery. The blood leucocyte count was 0.98 ± 0.2 × 10(3)/mm(3) vs. 5.85 ± 0.9 × 10(3)/mm(3) in patients with peripheral cytopenia compared to non-cytopenic patients (p<0.01). There was a statistically important difference in duration of intensive care unit stay between the 2 groups (p<0.01). A correlation between tacrolimus serum concentration and risk for leucopenia was also detected (p<0.05). Conclusions: Basiliximab administration as induction therapy, tacrolimus serum concentration, and duration of intensive care unit stay are risk factors for leucopenia.

Costanzo MR: Midwest Heart Foundation, Lombard Illinois, USA Dipchand A: Hospital for Sick Children, Toronto Ontario, Canada; Starling R: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Anderson A: University of Chicago, Chicago, Illinois, USA; Chan M: University of Alberta, Edmonton, Alberta, Canada; Desai S: Inova Fairfax Hospital, Fairfax, Virginia, USA; Fedson S: University of Chicago, Chicago, Illinois, USA; Fisher P: Ochsner Clinic, New Orleans, Louisiana, USA; Gonzales-Stawinski G: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Martinelli L: Ospedale Niguarda, Milano, Italy; McGiffin D: University of Alabama, Birmingham, Alabama, USA; Parisi F: Ospedale Pediatrico Bambino Ges霉, Rome, Italy; Smith J: Freeman Hospital, Newcastle upon Tyne, UK Taylor D: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Meiser B: University of Munich/Grosshaden, Munich, Germany; Baran D: Newark Beth Israel Medical Center, Newark, New Jersey, USA; Carboni M: Duke University Medical Center, Durham, North Carolina, USA; Dengler T: University of Hidelberg, Heidelberg, Germany; Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, USA; Frigerio M: Ospedale Niguarda, Milano, Italy; Kfoury A: Intermountain Medical Center, Murray, Utah, USA; Kim D: University of Alberta, Edmonton, Alberta, Canada; Kobashigawa J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Shullo M: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Stehlik J: University of Utah, Salt Lake City, Utah, USA; Teuteberg J: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Uber P: University of Maryland, Baltimore, Maryland, USA; Zuckermann A: University of Vienna, Vienna, Austria. Hunt S: Stanford University, Palo Alto, California, USA; Burch M: Great Ormond Street Hospital, London, UK; Bhat G: Advocate Christ Medical Center, Oak Lawn, Illinois, USA; Canter C: St. Louis Children Hospital, St. Louis, Missouri, USA; Chinnock R: Loma Linda University Children's Hospital, Loma Linda, California, USA; Crespo-Leiro M: Hospital Universitario A Coru帽a, La Coru帽a, Spain; Delgado R: Texas Heart Institute, Houston, Texas, USA; Dobbels F: Katholieke Universiteit Leuven, Leuven, Belgium; Grady K: Northwestern University, Chicago, Illlinois, USA; Kao W: University of Wisconsin, Madison Wisconsin, USA; Lamour J: Montefiore Medical Center, New York, New York, USA; Parry G: Freeman Hospital, Newcastle upon Tyne, UK; Patel J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Pini D: Istituto Clinico Humanitas, Rozzano, Italy; Pinney S: Mount Sinai Medical Center, New York, New York, USA; Towbin J: Cincinnati Children's Hospital, Cincinnati, Ohio, USA; Wolfel G: University of Colorado, Denver, Colorado, USA Delgado D: University of Toronto, Toronto, Ontario, Canada; Eisen H: Drexler University College of Medicine, Philadelphia, Pennsylvania, USA; Goldberg L: University of Pennsylvania, Philadelphia, Pennsylvania, USA; Hosenpud J: Mayo Clinic, Jacksonville, Florida, USA; Johnson M: University of Wisconsin, Madison, Wisconsin, USA; Keogh A: St Vincent Hospital, Sidney, New South Wales, Australia; Lewis C: Papworth Hospital Cambridge, UK; O'Connell J: St. Joseph Hospital, Atlanta, Georgia, USA; Rogers J: Duke University Medical Center, Durham, North Carolina, USA; Ross H: University of Toronto, Toronto, Ontario, Canada; Russell S: Johns Hopkins Hospital, Baltimore, Maryland, USA; Vanhaecke J: University Hospital Gasthuisberg, Leuven, Belgium.

We recently reported that Wuzhi tablet (WZ; Schisandra sphenanthera extract) can inhibit P-glycoprotein (P-gp)-mediated efflux and CYP3A-mediated metabolism of tacrolimus (FK506) and thus increase the blood concentrations of FK506. Major active lignans of WZ include schisandrin A, schisandrin B, schisandrin C, schisandrol A, schisandrol B, and schisantherin A. Whether and how these six lignans affect the pharmacokinetics of FK506 remains unclear. Therefore, this study aimed to investigate the effects of these lignans on the first-pass absorption and metabolism of FK506 and the involved mechanisms in vitro and in vivo. The results showed that whole-blood concentrations of FK506 were increased to different degrees following coadministration of the six lignans, respectively. Schisandrol B showed the strongest effect on the increase of the area under the concentration-time curve, the oral bioavailability, the gut processes affecting availability, and the hepatic availability of FK506. The reduction of intestinal first-pass effect contributed most to the increase in oral bioavailability of FK506 when coadministered with schisandrol B. In vitro transport experiment showed that schisandrin A, schisandrin B, and schisandrol B inhibited P-gp-mediated efflux of FK506. In vitro metabolism study showed that the inhibitory effect of these six lignans on FK506 metabolism was dose-dependent. In conclusion, the exposure of FK506 in rats was increased when coadministered with these lignans, and schisandrol B showed the strongest effect. Lignans of WZ inhibited P-gp-mediated efflux and CYP3A-mediated metabolism of FK506, and the reduction of intestinal first-pass affected by the lignans was the major cause of the increased FK506 oral bioavailability.