(1R,9S,12S,13R,14R,17R,18Z,21R,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 | 104987-11-3

• 物质功能分类: 生物化工 - 抑制剂 - 免疫抑制剂
• 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: (1R,9S,12S,13R,14R,17R,18Z,21R,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
• 英文别名: (1R,9S,12S,13R,14S,17R,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
• CAS: 104987-11-3
• 化学式: C₄₄H₆₉NO₁₂
• 分子量: 804.0
• InChiKey: QJJXYPPXXYFBGM-KVDYWLTISA-N

物化性质

• 熔点：
  113-115°C
• 沸点：
  871.7±75.0 °C(Predicted)
• 密度：
  1.19±0.1 g/cm3(Predicted)
• 闪点：
  2℃
• 溶解度：
  二甲基亚砜：>3 mg/mL
• 蒸汽压力：
  8.37X10-32 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable under recommended storage conditions. /FK-506 monohydrate/
• 解离常数：
  pKa1 = 2.94; pKa2 = 9.95; pKa3 = 14.07 (est)

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确定为主要生物转化机制。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

• 相互作用

在给予同等剂量的吗替麦考酚酯（MPA）产品时，与环孢素联合使用相比，与普罗graf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。临床医生应当注意，在接受MPA含有产品的患者从环孢素转换为普罗graf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增加，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。当使用CYP3A抑制剂或诱导剂给予普罗格拉夫时，可能需要调整剂量，并经常监测他克莫司全血谷浓度。此外，应监测患者的不良反应，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)

毒理性

• 相互作用

维拉帕米、地尔硫卓、硝苯地平和尼卡地平抑制他克莫司的CYP3A代谢，可能会增加他克莫司的全血浓度。当这些钙通道阻滞剂与他克莫司同时使用时，建议监测全血浓度并适当调整他克莫司的剂量。

Verapamil, diltiazem, nifedipine, and nicardipine inhibit CYP3A metabolism of tacrolimus and may increase tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these calcium channel blocking drugs and tacrolimus are used concomitantly.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

鉴定和使用：他克莫司是一种白色至类白色的结晶性粉末。它是一种钙神经素抑制剂免疫抑制剂，有几种制剂。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。他克莫司局部软膏用作非免疫受损成人和儿童的轻至重度异位性皮炎的短期和非连续慢性治疗的二线疗法。人类暴露和毒性：虽然大多数急性他克莫司过量（高达预期剂量的30倍）无症状，且所有患者均无后遗症恢复，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，尤其是皮肤，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，甚至致命的后果。虽然没有足够且良好的孕妇研究，但在人类怀孕期间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：大鼠和狒狒在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后的毒性在较低剂量下就明显，对大鼠和狒狒均如此。在大鼠中观察到比狒狒更低的剂量出现毒性。主要靶器官是肾脏、胰岛细胞和外分泌胰腺、脾脏、胸腺、胃肠道的淋巴结。此外，还观察到红细胞参数的降低。他克莫司还在大鼠和兔中产生了生殖和发育毒性。在大鼠中，长期口服高剂量的他克莫司导致性器官的改变以及青光眼/眼部变化。口服剂量为1和3.2 mg/kg/天的大鼠表现出明显的亲代毒性以及大鼠生育力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、着床数量减少、着床后损失的发生率增加以及胚胎和后代存活率降低。在兔畸胎学研究中，所有口服剂量的他克莫司（0.1、0.32或1 mg/kg/天）都产生了母体毒性迹象，包括体重减轻。剂量为0.32和1 mg/kg/天的他克莫司产生了发育毒性的迹象，如着床后损失的发生率增加、活胎数量减少以及形态变异的发生率增加。在大鼠畸胎学研究中，3.2 mg/kg/天的剂量观察到着床后损失增加。母体剂量为1 mg/kg/天的F1后代体重减轻。在母体剂量为3.2 mg/kg/天的情况下，F1后代的体重减轻、存活数量减少以及一些骨骼改变。他克莫司在体外细菌试验中未表现出遗传毒性活性，试验对象为沙门氏菌和李斯特菌，以及中国仓鼠肺细胞试验。在CHO/HGPRT试验（中国仓鼠卵巢细胞试验（CHO），测量HGPRT位点的正向突变）的体外试验和小鼠的体内试验中，没有观察到突变性的证据。他克莫司也未在啮齿类动物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)

吸收、分配和排泄

本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名婴儿为纯母乳喂养。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、脐带血以及产后母亲、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的量可以忽略不计。母乳喂养似乎不会减缓婴儿从他克莫司在出生时较高水平的下降。

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。分娩时脐带静脉血中Tacrolimus的平均（±SD）浓度（6.6 ± 1.8 ng/ml）是母体浓度（9.0 ± 3.4 ng/ml）的71 ± 18%（范围45-99%）。脐带静脉血浆的平均浓度（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。Tacrolimus在动脉脐带血中的浓度是脐静脉浓度的100 ± 12%。此外，婴儿通过母乳接触Tacrolimus的量不到母亲体重调整剂量的0.3%。母体和脐带Tacrolimus浓度之间的差异可能部分由胎盘P-gp功能、静脉脐带血中更大的红细胞分配和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

在分娩后立即（0-3天）从六位女性中获得了十份初乳样本，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的浓度范围内不依赖于浓度。tacrolimus主要与白蛋白和α-1-酸性糖蛋白结合，并与红细胞高度结合。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年会系统性累积。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)

安全信息

• 危险等级：
  6.1
• 危险品标志：
  Xi,T
• 安全说明：
  S26,S36,S45
• 危险类别码：
  R36/37/38,R25
• WGK Germany：
  3
• 海关编码：
  29349990
• 危险品运输编号：
  UN 2811 6.1/PG 3
• RTECS号：
  KD4201200
• 危险类别：
  6.1
• 包装等级：
  III
• 危险性防范说明：
  P264,P270,P301+P310+P330,P405,P501
• 危险性描述：
  H301

制备方法与用途

他克莫司是一种大环内酯类免疫抑制剂,主要通过以下机制发挥作用:

1. 与FK506结合蛋白(FKBP)形成复合体。

2. 降低T细胞中肽酰脯氨酰异构酶活性。

3. 抑制白细胞介素-2的合成。

4. 主要用于预防器官移植后的排异反应,对急性排异反应疗效更佳。

他克莫司的生产工艺如下:

1. 发酵生产:从Streptomyces tsukubaensis菌种发酵得到。

2. 提取分离:将发酵液过滤后用丙酮提取,通过树脂柱层析纯化。

3. 净化:经过硅胶色谱和反相高效液相色谱进一步纯化。

4. 结晶:浓缩溶液重结晶得到无色棱状结晶的纯品。

他克莫司的主要用途:

1. 器官移植后预防排异反应

2. 治疗某些自身免疫性疾病,如肾炎、视网膜炎等

需要注意的是,他克莫司是一种处方药,需在医生指导下使用。由于其较强的免疫抑制作用,可能存在感染风险和肾毒性等不良反应。