FK506

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯内酰胺
• 英文名称: FK506
• 英文别名: tacrolimus；[3S-[3R[E-(1S*,3S*,4S*)],3S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]-6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone；Tacrolimus-Bio-X；(1R,9S,12S,13R,14S,18E,21S,23S,24R,25S,27R)-1,14-dihydroxy-12-[(E)-1-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]prop-1-en-2-yl]-23,25-dimethoxy-13,19,21,27-tetramethyl-17-prop-2-enyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone
• 化学式: C₄₄H₆₉NO₁₂
• 分子量: 804.031
• InChiKey: QJJXYPPXXYFBGM-OVFAVTNISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  57
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  178
• 氢给体数：
  3
• 氢受体数：
  12

ADMET

代谢

他克莫司通过混合功能氧化酶系统广泛代谢，主要是细胞色素P-450系统（CYP3A）。已经提出了一个代谢途径，形成8种可能的代谢物。在体外实验中，去甲基化和羟基化被识别为生物转化的主要机制。在人肝微粒体培养中确定的主要代谢物是13-去甲基他克莫司。在体外研究中，据报道，31-去甲基代谢物具有与他克莫司相同的活性。

Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：他克莫司是一种白色至类白色的结晶性粉末。它是一种可抑制钙调神经蛋白的免疫抑制剂，有几种制剂形式。他克莫司的口服胶囊和静脉注射溶液用于预防接受肝脏、肾脏或心脏移植的患者器官排斥。他克莫司外用软膏作为二线治疗，用于非免疫受损的成人和儿童中至重度特应性皮炎的短期和非连续性慢性治疗。人类暴露和毒性：尽管大多数急性他克莫司过量（达到预期剂量的30倍）是无症状的，所有患者都无后遗症恢复，但一些急性过量后出现了不良反应，包括震颤、肾功能异常、高血压和周围性水肿。在治疗剂量下，接受他克莫司治疗的患者发展淋巴瘤和其他恶性肿瘤的风险增加，特别是皮肤肿瘤，以及发展细菌、病毒、真菌和原生动物感染的风险增加，包括机会性感染。这些感染可能导致严重，包括致命的后果。尽管没有对孕妇进行充分且良好控制的研究，但在人类中使用他克莫司与新生儿高钾血症和肾功能不全有关。动物研究：在大鼠和狒狒口服或静脉注射他克莫司后，表现出类似的毒理学特征。静脉给药后的毒性比口服给药更明显，对于大鼠和狒狒都是如此。大鼠比狒狒在更低剂量下表现出毒性。主要靶器官是肾脏、兰格汉斯岛的胰岛和外分泌胰腺、脾脏、胸腺、胃肠道和淋巴结。此外，还观察到了红细胞参数的降低。他克莫司在大鼠和家兔中也产生了生殖和发育毒性。在大鼠中，长期口服他克莫司高剂量导致性别器官的改变，以及青光眼/眼睛变化。口服他克莫司1毫克/千克/天和3.2毫克/千克/天的剂量在大鼠中产生了明显的亲本毒性以及生育和一般生殖性能的改变。对生殖的影响包括一些胚胎致死性、着床数减少、着床后损失增加以及胚胎和后代存活率降低。在家兔的致畸学研究中，所有口服他克莫司的剂量（0.1、0.32或1毫克/千克/天）都产生了母体毒性迹象，包括体重减轻。0.32毫克/千克/天和1毫克/千克/天的剂量产生了发育毒性迹象，如着床后损失增加、存活胎儿数减少和形态变异发生率增加。在大鼠的致畸学研究中，3.2毫克/千克/天的剂量观察到了着床后损失增加。母体剂量1毫克/千克/天降低了F1后代的体重。在母体剂量3.2毫克/千克/天时，F1后代出现了体重减轻、存活数减少和一些骨骼改变。他克莫司在体外细菌试验（鼠伤寒沙门氏菌和大肠杆菌）和哺乳动物试验（中国仓鼠肺细胞）中没有表现出致突变活性。在体外CHO/HGPRT试验（中国仓鼠卵巢细胞试验，测量HGPRT位点的正向突变）或体内小鼠的致突变性试验中也没有观察到致突变性。他克莫司也没有在大鼠肝细胞中引起非计划性DNA合成。

IDENTIFICATION AND USE: Tacrolimus is white to off-white crystalline powder. It is a calcineurin-inhibitor immunosuppressant available in several preparations. Tacrolimus in both oral capsules and a solution for IV injection is used for prophylaxis of organ rejection in patients receiving liver, kidney or heart transplants. Tacrolimus topical ointment is used as a second-line therapy for the short-term and non-continuous chronic treatment of moderate to severe atopic dermatitis in non-immunocompromised adults and children. HUMAN EXPOSURE AND TOXICITY: While most acute overdosages of tacrolimus at up to 30 times the intended dose have been asymptomatic and all patients recovered with no sequelae, some acute overdosages were followed by adverse reactions including tremors, abnormal renal function, hypertension, and peripheral edema. At therapeutic doses, patients receiving tacrolimus are at increased risk of developing lymphomas and other malignancies, particularly of the skin, as well as an increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. While there are no adequate and well-controlled studies in pregnant women, the use of tacrolimus during pregnancy in humans has been associated with neonatal hyperkalemia and renal dysfunction. ANIMAL STUDIES: Both rats and baboons showed a similar toxicologic profile following oral or intravenous administration of tacrolimus. Toxicity following intravenous administration was evident at lower doses than after oral administration for both rats and baboons. Toxicity was seen at lower doses in rats than in baboons. The primary target organs were the kidneys, pancreatic islets of Langerhans and exocrine pancreas, spleen, thymus, gastrointestinal tract, and lymph nodes. In addition, decreases in erythrocyte parameters were seen. Tacrolimus also produced reproductive and developmental toxicity in both rats and rabbits. In rats, chronic oral administration of tacrolimus at high doses resulted in changes in sex organs, and glaucoma/eye changes. Oral doses of tacrolimus at 1 and 3.2 mg/kg/day produced overt signs of parental toxicity and changes in the fertility and general reproductive performance of rats. Effects on reproduction included some embryo lethality, reduced number of implantations, increased incidence of post-implantation loss, and reduced embryo and offspring viability. In a rabbit teratology study, signs of maternal toxicity including reduced body weight were produced at all oral doses of tacrolimus administered (0.1, 0.32, or 1 mg/kg/day). Doses of 0.32 and 1 mg/kg/day produced signs of developmental toxicity, such as increased incidence of post-implantation losses, reduced number of viable fetuses, and increased incidences of morphological variations. In a rat teratology study, increased post-implantation loss was observed at 3.2 mg/kg/day. Maternal doses of 1 mg/kg/day decreased the body weight of F1 offspring. Decreased body weight, reduced survival number, and some skeletal alterations were seen in F1 offspring at maternal doses of 3.2 mg/kg/day. Tacrolimus did not exhibit genotoxic activity in vitro in bacterial asaays in Salmonella typhimurium and Escherichia coli or mammalian assays in Chinese hamster lung-derived cells assays. No evidence of mutagenicity was observed in vitro in the CHO/HGPRT assay (the Chinese hamster ovary cell assay (CHO), which measures forward mutation of the HGPRT locus) or in vivo in clastogenicity assays performed in mice. Tacrolimus also did not cause unscheduled DNA synthesis in rodent hepatocytes.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：有限的数据表明，系统给药的Tacrolimus在母乳中的含量较低，可能不会对哺乳婴儿产生不利影响。美国和欧洲的专家和指南认为，在母乳喂养期间使用Tacrolimus可能是安全的。如果在此期间使用此药物，应监测仅以母乳喂养的婴儿，可能包括测量血清水平以排除毒性的担忧。 局部Tacrolimus的风险较低，因为其在局部应用后吸收不良，大多数患者的峰值血药浓度低于2 mcg/L。确保婴儿的皮肤不直接接触已治疗的皮肤区域。如果要治疗乳房，首选其他药物；在哺乳期间不要涂抹在乳头区域。最新的欧洲指南允许在哺乳后立即涂抹Tacrolimus，并在哺乳前轻轻仔细清洁乳头。 ◉ 对哺乳婴儿的影响：一名婴儿在母亲Tacrolimus治疗期间全程至至少2.5个月大时仅以母乳喂养，此时婴儿在身体和神经方面发育正常。婴儿的胸腺超声检查正常。 国家移植妊娠登记处报告了1991年至2011年间收集的数据，这些数据来自移植后母乳喂养婴儿的母亲。共有68位移植母亲（大多数是肾脏或肝脏移植）在母乳喂养总共83名婴儿期间使用了Tacrolimus。哺乳期从1周到1.5年不等，对儿童的随访时间从几周到16年不等。所有婴儿或儿童均未报告问题。截至2013年12月，共有92位母亲母乳喂养了125名婴儿，最长26个月，婴儿未出现明显不良反应。 六位在怀孕期间因器官移植而服用Tacrolimus的妇女哺乳了她们的婴儿（4名完全哺乳，2名部分哺乳），哺乳期从45天到180天，随访期从2个月到30个月。哺乳期间母亲平均每日Tacrolimus剂量为9.6毫克（每日剂量范围为4.5至15毫克）。四位母亲还每天服用100至150毫克的硫唑嘌呤，一名服用地尔硫卓，一名服用15毫克泼尼松和75毫克阿司匹林。尽管一名婴儿在继续哺乳的情况下出现了短暂的血小板增多症，但所有婴儿均未出现明确的Tacrolimus相关副作用。发育里程碑正常，未发现感染模式。 报告了两名患有系统性红斑狼疮的妇女，在怀孕和哺乳期间每天服用3毫克Tacrolimus以及30或40毫克泼尼松。出生三年后，两个孩子都很健康。哺乳期的持续时间未说明。 在一项长达25年的肝移植妇女的病例系列中，一名妇女在服用Tacrolimus期间哺乳了她的婴儿（哺乳程度未说明）。未注意到新生儿并发症。 一名患有肝移植的妇女在维持治疗中使用了Belatacept 10毫克/千克每月，缓释Tacrolimus（Envarsus和Veloxis）2毫克每日，硫唑嘌呤25毫克每日，泼尼松2.5毫克每日。她为她的婴儿哺乳了一年（哺乳程度未说明）。婴儿的生长和认知里程碑正常。 一项澳大利亚病例系列报告了3名心脏移植的妇女，共有5名婴儿，在母亲Tacrolimus治疗期间均接受了哺乳（哺乳程度未说明）。每日剂量范围为3至13毫克。在出院前未报告婴儿不良反应。 一名对依那西普耐药的类风湿性关节炎妇女在怀孕期间直到37周妊娠期每两周服用200毫克Sarilumab。她还每天服用10毫克泼尼松和3毫克Tacrolimus。她在38周妊娠期分娩了一个健康的婴儿并哺乳了她。产后继续服用泼尼松，Tacrolimus在产后7天重新开始服用，Sarilumab在产后28天重新开始服用。母亲在产后6个月继续哺乳。婴儿在达到六个月后接种了多种活疫苗，包括卡介苗，没有不良反应。 ◉ 对哺乳和母乳的影响：截至修订日期，未找到相关已发布信息。

◉ Summary of Use during Lactation:Limited data indicate that amounts of systemically administered tacrolimus are low in breastmilk and probably do not adversely affect the breastfed infant. United States and European experts and guidelines consider tacrolimus to be probably safe to use during breastfeeding. Exclusively breastfed infants should be monitored if this drug is used during lactation, possibly including measurement of serum levels to rule out toxicity if there is a concern. Topical tacrolimus presents a low risk to the nursing infant because it is poorly absorbed after topical application and peak blood concentrations are less than 2 mcg/L in most patients. Ensure that the infant's skin does not come into direct contact with the areas of skin that have been treated. If the breast is to be treated, an alternate drug is preferred; do not apply to the nipple area while nursing. A newer European guideline allows tacrolimus to be applied just after nursing, with the nipples cleaned gently and carefully before nursing. ◉ Effects in Breastfed Infants:One infant was exclusively breastfed during maternal tacrolimus therapy throughout gestation to at least 2.5 months of age at which time the infant was developing normally physically and neurologically. An ultrasound examination of the infant's thymus was normal. The National Transplantation Pregnancy Registry reported data gathered from 1991 to 2011 on mothers who breastfed their infants following organ transplantation. A total of 68 mothers with transplants (mostly kidney or liver) used tacrolimus while breastfeeding a total of 83 infants. Duration of nursing ranged from 1 week to 1.5 years and follow-up of the children ranged from weeks to 16 years. There were no reports of problems in any of the infants or children. As of December 2013, a total of 92 mothers had breastfed 125 infants for as long as 26 months with no apparent adverse effects in infants. The breastfed infants of six women who took tacrolimus during pregnancy for organ transplantation were breastfed (4 exclusive, 2 partial) for 45 to 180 days and followed for periods of 2 to 30 months. The mothers' mean daily tacrolimus dosage during breastfeeding was 9.6 mg daily (range 4.5 to 15 mg daily). Four mothers were also taking azathioprine 100 to 150 mg daily, one was taking diltiazem, and one was taking prednisolone 15 mg and aspirin 75 mg daily. None of the infants had any clear tacrolimus-related side effects, although one had transient thrombocytosis that resolved despite continued breastfeeding. Developmental milestones were normal and no pattern of infections was noted. Two mothers with systemic lupus erythematosus were reported who took tacrolimus 3 mg daily during pregnancy and lactation as well as prednisolone 30 or 40 mg daily. Three years after birth, both children were healthy. The durations of lactation were not stated. In a case series of women who had liver transplants over a 25-year period, one woman breastfed (extent not stated) her infant while taking tacrolimus. No neonatal complications were noted. A mother with a liver transplant was maintained on belatacept 10 mg/kg monthly, slow-release tacrolimus (Envarsus and Veloxis) 2 mg daily, azathioprine 25 mg daily, and prednisone 2.5 mg daily. She breastfed her infant for a year (extent not stated). The infant’s growth and cognitive milestones were normal. An Australian case series reported 3 women with heart transplants who had a total of 5 infants, all of whom were breastfed (extent not stated) during maternal tacrolimus therapy. Daily dosages ranged from 3 to 13 mg daily. No adverse infant effects were reported up to the times of discharge. A woman with rheumatoid arthritis refractory to etanercept took sarilumab 200 mg every two weeks during pregnancy until 37 weeks of gestation. She was also taking prednisolone 10 mg and tacrolimus 3 mg daily. She delivered a healthy infant at 38 weeks of gestation and breastfed her infant. Prednisolone was continued postpartum, tacrolimus was restarted at 7 days postpartum, and sarilumab was restarted at 28 days postpartum. The mother continued to breastfeed until 6 months postpartum. The infant was vaccinated with multiple live vaccines after reaching six months old, including the Bacille-Calmette-Guerin vaccine, with no adverse effects. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

在使用相同剂量的吗替麦考酚酯（MPA）产品时，与环孢素联合使用相比，与普乐可复联合使用时MPA的暴露量更高，因为环孢素会中断MPA的肠肝循环，而他克莫司则不会。临床医生应该意识到，在接受MPA含有产品的患者从环孢素转换为普乐可复后，也存在MPA暴露量增加的潜在可能性。

With a given dose of mycophenolic acid (MPA) products, exposure to MPA is higher with Prograf co-administration than with cyclosporine co-administration because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Clinicians should be aware that there is also a potential for increased MPA exposure after crossover from cyclosporine to Prograf in patients concomitantly receiving MPA-containing products.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

葡萄柚汁抑制CYP3A-酶，导致他克莫司全血谷浓度升高，患者应避免在服用他克莫司时食用葡萄柚或饮用葡萄柚汁。

Grapefruit juice inhibits CYP3A-enzymes resulting in increased tacrolimus whole blood trough concentrations, and patients should avoid eating grapefruit or drinking grapefruit juice with tacrolimus.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

由于他克莫司主要通过CYP3A酶代谢，已知抑制这些酶的药物或物质可能会增加他克莫司的全血浓度。已知诱导CYP3A酶的药物可能会降低他克莫司的全血浓度。当与CYP3A抑制剂或诱导剂一起使用普罗格拉夫时，可能需要调整剂量并经常监测他克莫司全血谷浓度。此外，患者应被监测是否有不良反应，包括肾功能变化和QT间期延长。

Since tacrolimus is metabolized mainly by CYP3A enzymes, drugs or substances known to inhibit these enzymes may increase tacrolimus whole blood concentrations. Drugs known to induce CYP3A enzymes may decrease tacrolimus whole blood concentrations. Dose adjustments may be needed along with frequent monitoring of tacrolimus whole blood trough concentrations when Prograf is administered with CYP3A inhibitors or inducers. In addition, patients should be monitored for adverse reactions including changes in renal function and QT prolongation.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

这项研究旨在评估哺乳期间母乳中他克莫司的水平和新生儿的暴露情况。在一项观察性队列研究中，对两个三级转诊高风险妇产医学诊所进行了研究。研究了14名在孕期和哺乳期服用他克莫司的妇女及其15名婴儿，其中11名婴儿是纯母乳喂养。通过液相色谱-串联质谱法分析他克莫司水平。在可能的情况下，收集了母亲、脐带血以及出生后母亲、婴儿和母乳的样本。所有进行系列抽样的婴儿的他克莫司水平都有下降，大约每天下降15%（几何平均浓度比率为0.85；95%置信区间，0.82-0.88；P<0.001）。母乳喂养的婴儿与奶瓶喂养的婴儿在他克莫司水平上没有差异（中位数为1.3微克/升[范围，0.0-4.0]对1.0微克/升[范围，0.0-2.3]；P=0.91）。从母乳中吸收的最大估计量为母亲剂量的0.23%（按体重调整）。通过母乳摄入他克莫司对婴儿的影响可以忽略不计。母乳喂养似乎不会减慢婴儿从他克莫司在出生时较高水平的下降速度。

The aim of this study was to assess tacrolimus levels in breast milk and neonatal exposure during breastfeeding. An observational cohort study was performed in two tertiary referral high-risk obstetric medicine clinics. Fourteen women taking tacrolimus during pregnancy and lactation, and their 15 infants, 11 of whom were exclusively breast-fed, were assessed. Tacrolimus levels were analyzed by liquid chromatography-tandem mass spectrometry. Samples from mothers and cord blood were collected at delivery and from mothers, infants, and breast milk postnatally where possible. All infants with serial sampling had a decline in tacrolimus level, which was approximately 15% per day (ratio of geometric mean concentrations 0.85; 95% confidence interval, 0.82-0.88; P<0.001). Breast-fed infants did not have higher tacrolimus levels compared with bottle-fed infants (median 1.3 ug/L [range, 0.0-4.0] versus 1.0 ug/L (range, 0.0-2.3), respectively; P=0.91). Maximum estimated absorption from breast milk is 0.23% of maternal dose (weight-adjusted). Ingestion of tacrolimus by infants via breast milk is negligible. Breastfeeding does not appear to slow the decline of infant tacrolimus levels from higher levels present at birth.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在分娩时，从八名实体器官异体移植受者获取了母体和脐带（静脉和动脉）样本，以测量血液和血浆中Tacrolimus（他克莫司）及其代谢物结合型和未结合型的浓度。在一个对象中评估了母乳中Tacrolimus的药代动力学。分娩时脐静脉血中Tacrolimus的平均（±SD）浓度（6.6 ± 1.8 ng/ml）为母体浓度（9.0 ± 3.4 ng/ml）的71 ± 18%（范围45-99%）。脐静脉血浆中Tacrolimus的平均浓度（0.09 ± 0.04 ng/ml）和未结合药物浓度（0.003 ± 0.001 ng/ml）大约是母体相应浓度的五分之一。脐动脉血中Tacrolimus的浓度是脐静脉浓度的100 ± 12%。此外，通过母乳接触Tacrolimus的婴儿暴露量不到母亲体重调整剂量的0.3%。母体和脐带Tacrolimus浓度的差异部分可以由胎盘P-gp功能、更大的红细胞分配和脐静脉血中更高的血细胞比容水平来解释。

Maternal and umbilical cord (venous and arterial) samples were obtained at delivery from eight solid organ allograft recipients to measure tacrolimus and metabolite bound and unbound concentrations in blood and plasma. Tacrolimus pharmacokinetics in breast milk were assessed in one subject. Mean (+ or - SD) tacrolimus concentrations at the time of delivery in umbilical cord venous blood (6.6 + or - 1.8 ng ml(-1)) were 71 + or - 18% (range 45-99%) of maternal concentrations (9.0 + or - 3.4 ng ml(-1)). The mean umbilical cord venous plasma (0.09 + or - 0.04 ng ml(-1)) and unbound drug concentrations (0.003 + or - 0.001 ng ml(-1)) were approximately one fifth of the respective maternal concentrations. Arterial umbilical cord blood concentrations of tacrolimus were 100 + or - 12% of umbilical venous concentrations. In addition, infant exposure to tacrolimus through the breast milk was less than 0.3% of the mother's weight-adjusted dose. Differences between maternal and umbilical cord tacrolimus concentrations may be explained in part by placental P-gp function, greater red blood cell partitioning and higher haematocrit levels in venous cord blood.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

从六位妇女在产后期（0-3天）获得的十个初乳样本中，平均药物浓度为0.79 ng/mL（范围0.3-1.9 ng/mL）。乳母血浆比率为0.5。

Ten colostrum samples were obtained from six women in the immediate postpartum period (0-3 days) with a mean drug concentration of 0.79 ng/mL (range 0.3-1.9 ng/mL). The median milk:maternal plasma ratio was 0.5.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

tacrolimus的血浆蛋白结合率约为99%，在5-50 ng/mL的浓度范围内与浓度无关。tacrolimus主要与白蛋白和α-1-酸性糖蛋白结合，并且与红细胞的结合力很高。tacrolimus在全血和血浆之间的分布取决于几个因素，如血细胞比容、血浆分离时的温度、药物浓度和血浆蛋白浓度。在美国的一项研究中，全血浓度与血浆浓度的比率平均为35（范围为12至67）。根据血液浓度，没有证据表明间歇性局部应用tacrolimus长达1年期间会在全身积累。与其他局部钙调神经磷酸酶抑制剂一样，尚不清楚tacrolimus是否分布到淋巴系统。

The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a US study, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67). There was no evidence based on blood concentrations that tacrolimus accumulates systemically upon intermittent topical application for periods of up to 1 year. As with other topical calcineurin inhibitors, it is not known whether tacrolimus is distributed into the lymphatic system.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  FK506 在 4-二甲氨基吡啶 、 氨 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 27.0h， 生成 (1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(1E)-1-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]prop-1-en-2-yl]-23,25-dimethoxy-1-ethylamino-14-hydroxy-13,19,21,27-tetramethyl-17-(prop-2-en-1-yl)-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone
  参考文献：
  名称：

  [EN] COMPOUNDS FOR THE INHIBITION OF A PROLYL ISOMERASE AND METHODS OF USE THEREOF
  [FR] COMPOSÉS POUR L'INHIBITION D'UNE PROLYL-ISOMÉRASE ET LEURS MÉTHODES D'UTILISATION

  摘要：

  提供了抑制Pin 1和/或FKBP的化合物以及使用方法。

  公开号：

  WO2018112435A1

文献信息

• Tacrolimus Combination Products
  申请人：Ranklove Lisbet Bonlokke

  公开号：US20090011013A1

  公开（公告）日：2009-01-08

  The present invention relates to a pharmaceutical composition comprising tacrolimus or an analogue thereof and a substance being a substrate for CYP3A4 and/or P-glycoprotein, oral solid dosage forms comprising the pharmaceutical composition such as tablets, methods for preparing the pharmaceutical composition and oral dosage forms and use of the pharmaceutical composition for preparing a medicament. The substance being a substrate for CYP3A4 and/or P-glycoprotein is preferably cyclosporine A. The invention further relates to treatment of a patient in need thereof by coadministration of the combination according to the invention. In a further aspect, the invention relates to the above combination further comprising a CYP3A4 inhibitor compound, preferably a compound naturally occurring in citrus juice, for example grapefruit juice, preferably a spiro ortho ester compound.
• NMR SYSTEMS AND METHODS FOR THE RAPID DETECTION OF ANALYTES
  申请人：T2 BIOSYSTEMS. INC.

  公开号：US20130266944A1

  公开（公告）日：2013-10-10

  This invention features systems and methods for the detection of analytes, and their use in the treatment and diagnosis of disease.
• US8173840B2
  申请人：——

  公开号：US8173840B2

  公开（公告）日：2012-05-08
• US8563298B2
  申请人：——

  公开号：US8563298B2

  公开（公告）日：2013-10-22
• US9046493B2
  申请人：——

  公开号：US9046493B2

  公开（公告）日：2015-06-02