(1R,9S,14S,18E,21S,23S,24R)-1,14-dihydroxy-12-[(E)-1-[(3R)-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,14S,18E,21S,23S,24R)-1,14-dihydroxy-12-[(E)-1-[(3R)-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-NRHFKKOMSA-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)
• 亨利常数：
  Henry's Law constant = 4.74X10-24 atm-cum/mol at 25 °C (est)
• 稳定性/保质期：

  Stable under recommended storage conditions. /FK-506 monohydrate/

• 旋光度：
  Colorless prisms from acetonitrile; mp 127-129 °C. Specific optical rotation: -84.4 deg at 23 °C/D (c = 1.02 in chloroform). Soluble in methanol, ethanol, acetone, ethyl acetate, chloroform, diethyl ether; sparingly soluble in hexane, petroleum ether. Insoluble in water. /Tacrolimus 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

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治疗。人类暴露和毒性：虽然大多数他克莫司的急性过量（高达预期剂量的30倍）是无症状的，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，特别是皮肤，以及发展细菌、病毒、真菌和原虫感染的风险增加，包括机会性感染。这些感染可能导致严重，包括致命的后果。虽然没有足够且控制良好的孕妇研究，但在人类怀孕期间使用他克莫司已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给药他克莫司后表现出类似的毒理学特征。静脉给药后的毒性在较低剂量下就比口服给药在大鼠和狒狒中更为明显。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、胰岛细胞和胰腺外分泌部分、脾脏、胸腺、胃肠道和淋巴结。此外，还观察到红细胞参数的减少。他克莫司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别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、植入数量减少、植入后损失的发生率增加以及胚胎和后代存活率降低。在兔的致畸研究中，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，如植入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。在大鼠的致畸研究中，3.2 mg/kg/天的剂量观察到植入后损失增加。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/天时，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属和大肠杆菌，以及中国仓鼠肺细胞衍生细胞的哺乳动物试验。在体外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）或小鼠体内进行的致突变试验中未观察到突变活性的证据。他克莫司也未在啮齿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)

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，因为环孢素会干扰MPA的肠肝循环，而他克莫司则不会。临床医生应该意识到，在患者从环孢素转换为普乐可复的同时接受含有MPA的产品时，也存在MPA暴露量增加的可能性。

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)

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了Tacrolimus的CYP3A代谢，可能会增加Tacrolimus的全血浓度。当这些钙通道阻滞剂与Tacrolimus同时使用时，建议监测全血浓度并根据情况调整Tacrolimus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)

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