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Tacrolimus
FK-506 · prograf · Protopic · Advagraf · Tacrolimus premix · Tacrolimus reference · imus) · Tacros
Identifikatoren & physikalische Daten
| CAS No. | 104987-11-3 |
|---|---|
| Summenformel | C44H69NO12 |
| Durchschnittliche Molmasse | 804 g/mol |
| Monoisotopische Masse | 803,48197665 g/mol |
| SMILES | C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC |
| InChIKey | QJJXYPPXXYFBGM-LFZNUXCKSA-N |
| PubChem CID | 445643 |
| ChEMBL | CHEMBL269732 |
| ChEBI | CHEBI:61049 |
| EC No. | 627-021-3 |
| DTXSID | DTXSID5046354 |
Chemische & physikalische Eigenschaften
| XLogP | 2,7 |
|---|---|
| Polarare Oberfläche (TPSA) | 178 |
| H-Brücken-Donoren | 3 |
| H-Brücken-Akzeptoren | 12 |
| Frei drehbare Bindungen | 7 |
| Schwere Atome | 57 |
| Formalladung | 0 |
| Komplexität | 1.480 |
| Lipide | Polyketides [PK] -> Macrolides and lactone polyketides [PK04] |
| Löslichkeit | InsolubleDMSO: >3 mg/mLFreely soluble in DMSO or ethanol. Poorly soluble in water.Soluble in dimethyl sulfoxide, ethanol, water, acetone, chloroform, ethyl acetate, ether, methanol and dimethyl formamide. |
| Human Drugs | Breast FeedingLactationMilk, HumanImmunosuppressive AgentsDermatologic AgentsFDA approved drugs -> Active ingredientEMA approved medicines: Human medicine |
| Optical Rotation | Colorless prisms from acetonitrilemp 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 ethersparingly soluble in hexane, petroleum ether. Insoluble in water. /Tacrolimus monohydrate/ |
| Stability/Shelf Life | Stable under recommended storage conditions. /FK-506 monohydrate/ |
| Collision Cross Section | 267 Ų [M+Na]+ [CCS Type: TWMethod: calibrated with polyalanine and drug standards]269.55 Ų [M+Na]+ [CCS Type: TW |
| Schmelzpunkt | 113-115°C |
| Siedepunkt | 871.7±75.0 °C(Predicted) |
| Dichte | 1.19±0.1 g/cm3(Predicted) |
| Flammpunkt | 2℃ |
| Lagerbedingungen | Sealed in dry,Store in freezer, under -20°C |
| Aggregatzustand | solid |
| pKa (Säurekonstante) | 9.97±0.70(Predicted) |
| Farbe | white |
| BCS Class | 2 |
| Stabilität | Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 2 months. |
| InChIKey | QJJXYPPXXYFBGM-LFZNUXCKSA-N |
| CAS Datenbank | 104987-11-3(CAS DataBase Reference) |
Sicherheit & Vorschriften
| GHS-Einstufung | DangerH301 (97.6%): Toxic if swallowed [Danger Acute toxicity, oral]P203, P260, P264, P270, P280, P301+P316, P318, P319, P321, P330, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 82 reports by companies from 13 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral] |
|---|---|
| Regulatorische Informationen | Hazard Traits - Carcinogenicity |
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tacrolimus, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. |
| Toxic Combustion Products | Special hazards arising from the substance or mixture: Carbon oxides, nitrogen oxides (NOx). /FK-506 monohydrate/ |
| Hazard Classes and Categories | Acute Tox. 3 (100%)Acute Tox. 3 (97.6%) |
| Hazardous Reactivities and Incompatibilities | Strong oxidizing agents. /FK-506 monohydrate/ |
| Brandbekämpfungsverfahren | Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. /FK-506 monohydrate/ |
| Lagerbedingungen | Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature: -20 °C Keep in a dry place. /FK-506 monohydrate/Store at 25 °C (77 °F)excursions permitted to 15 °C-30 °C (59 °F-86 °F).Store at room temperature 25 °C (77 °F)excursions permitted to 15 deg - 30 °C (59 deg - 86 °F). |
| Reinigungsverfahren | Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapours, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /FK-506 monohydrate/ |
| Entsorgungsverfahren | SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Contaminated packaging: Dispose of as unused product. /FK-506 monohydrate/ |
| Preventive Measures | Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N99 (US) or type P2 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /FK-506 monohydrate/Complete suit protecting against chemicals, The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /FK-506 monohydrate/Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /FK-506 monohydrate/Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. /FK-506 monohydrate/SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker. |
| Personal Protective Equipment (PPE) | Handle with gloves. /FK-506 monohydrate/Face shield and safety glasses Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /FK-506 monohydrate/ |
| Wechselwirkungen | 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.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.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.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.For more Interactions (Complete) data for Tacrolimus (18 total), please visit the HSDB record page. |
| Hepatotoxicity | Tacrolimus therapy is associated with mild to moderate elevations in serum aminotransferase levels in 5% to 10% of patients. These elevations are usually mild, asymptomatic and self-limited, but are occasionally persistent and may require dose modification. Tacrolimus has also been implicated in instances of cholestatic hepatitis, but clinically apparent liver injury is rare. Because tacrolimus is used in the context of organ transplantation and often in liver transplantation, the causes of liver test abnormalities arising during therapy are many, and drug induced liver injury due to tacrolimus is sufficiently rare that its clinical features and typical course have not been defined. |
| Unerwünschte Wirkungen | Adverse effects include, but are not limited to: |
| Expositionspfade | Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability in adult kidney transplant patients is 17Њ±10%in adults liver transplant patients is 22Њ±6%in healthy subjects is 18Њ±5%. The absolute bioavailability in pediatric liver transplant patients was 31Њ±24%. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg. When given without food, the rate and extent of absorption were the greatest. The time of the meal also affected bioavailability. When given immediately after a meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition. |
| Milk Concentrations | EXPERIMENTAL: ... Very small amounts of tacrolimus are excreted in the breast milk ... .EXPERIMENTAL: 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 0.8595% confidence interval, 0.82-0.88P<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), respectivelyP=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.EXPERIMENTAL: ... Infant exposure to tacrolimus through the breast milk was less than 0.3% of the mother's weight-adjusted dose. ...EXPERIMENTAL: Although systemic absorption of tacrolimus following topical applications of Protopic Ointment is minimal relative to systemic administration, it is known that tacrolimus is excreted in human milk. ... |
| Toxizitätsübersicht | 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.Signs and Symptoms of OverdoseThe mechanism of action of tacrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This prevents the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines. Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-, all of which are involved in the early stages of T-cell activation. Additionally, tacrolimus has been shown to inhibit the release of pre-formed mediators from skin mast cells and basophils, and to downregulate the expression of FceRI on Langerhans cells. |
| Signs and Symptoms | Side effects can be severe and include blurred vision, liver and kidney problems (it is nephrotoxic), seizures, tremors, hypertension, hypomagnesemia, diabetes mellitus, hyperkalemia, itching, insomnia, confusion. |
| Natural Pollution Sources | Tacrolimus is derived from a soil bacteria, Streptomyces tsukubaensis(1). |
| Human Toxicity Excerpts | /SIGNS AND SYMPTOMS/ Patients receiving immunosuppressants, including Prograf, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes./SIGNS AND SYMPTOMS/ Patients receiving immunosuppressants, including Prograf, are at increased risk of developing lymphomas and other malignancies, particularly of the skin [see Boxed Warning]. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent./SIGNS AND SYMPTOMS/ 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./SIGNS AND SYMPTOMS/ Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions ... including tremors, abnormal renal function, hypertension, and peripheral edema)in one case of acute overdosage, transient urticaria and lethargy were observed.For more Human Toxicity Excerpts (Complete) data for Tacrolimus (11 total), please visit the HSDB record page. |
| Carcinogen Classification | TacrolimusGroup 1: Carcinogenic to humansVolume 137: (2026) Hydrochlorothiazide, Voriconazole, and Tacrolimus2026 online2024No indication of carcinogenicity to humans (not listed by IARC). |
| Drug Induced Liver Injury | Drug Induced Liver Injury Rank (DILIrank 2.0)TacrolimusvLess-DILI-concern5Adverse reactionsDOI:10.1016/j.drudis.2016.02.015 |
| Non-Human Toxicity Excerpts | /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In a 52-week photocarcinogenicity study, the median time to onset of skin tumor formation was decreased in hairless mice following chronic topical dosing with concurrent exposure to UV radiation (40 weeks of treatment followed by 12 weeks of observation) with tacrolimus ointment at > or = 0.1% tacrolimus./LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% - 3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/sq m/day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown./LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ The carcinogenicity potential of FK506 /Sandoz Tacrolimus/ has been evaluated in mice and rats. Mice (56/sex) were administered FK506 as a dietary admix at doses of 0 (control), 0 (placebo), 0.3, 1 and 3 mg/kg/day. There was no evidence of any tumorigenic potential of FK506 in this study. Signs of toxicity were evident in the form of reduced bodyweight gain in both sexes receiving 3.0 mg/kg/day and for males receiving 1 mg/kg/day. For males receiving 3.0 mg/kg/day, there was a reduction in the efficiency of food utilization. An increase in mortality for males at 3.0 mg/kg/day was accompanied by pathological findings of minimal adipose tissue and fur staining, evidence of dysfunctional testes/epididymides, prostate glands and seminal vesicles. Males and females at 3.0 mg/kg/day also demonstrated reduced islets of Langerhans and increased basophilia and cellularity of islets. The no-effect level was considered to be 0.3 mg/kg/day in both sexes. In addition, 1 mg/kg/day was a no-effect level for females only./LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ The 104 week studies in rats administered tacrolimus at oral doses of 0.2, 0.5, 1.25, 2.5 and 5.0 mg/kg/day demonstrated no evidence of tumorigenicity.For more Non-Human Toxicity Excerpts (Complete) data for Tacrolimus (11 total), please visit the HSDB record page. |
| Wassergefährdungsklasse (WGK) | 3 |
| UN-Transportnummer | UN 2811 6.1/PG 3 |
| Zollcode | 29349990 |
| RTECS-Nr. | KD4201200 |
| R-Sätze (R) | 25-36/37/38-36-20/21/22-11 |
| Gefahrensymbole | T,Xi,Xn,F |
| Sicherheitshinweise (S) | 45-36-26-36/37-16-60-20 |
| Gefahrenklasse | 6.1Acute Tox. 3 OralEye Irrit. 2Repr. 2STOT RE 2 |
| Lagerklasse | 6.1C - Combustible acute toxic Cat.3toxic compounds or compounds which causing chronic effects |
| Gefahrstoffdaten | 104987-11-3(Hazardous Substances Data) |
Anwendungen & Verwendung
Beschreibung
Tacrolimus, isolated from the microorganism Streptomyces tsukubaensis, is a macrolide immunosuppressant developed by Fujisawa for organ transplantation. It displays similar but more potent immunosuppressive activity than cyclosporin. It inhibits both cell mediated and humoral immune responses. In animal models of organ transplantation, tacrolimus has been shown to prolong survival of hepatic, renal, cardiac, small intestine, pancreatic and skin allografts and to reverse cardiac and renal allograft rejection. It has been used effectively in humans as rescue or primary immunosuppressant therapy in liver or kidney transplantation. Compared to cyclosporin, tacrolimus causes reduced incidence of infectious complications and of hypertension and hypercholesterolemia for the allograft recipients. In common with cyclosporin, tacrolimus binds with high affinity to a family of cytoplasmic immunosuppressant binding proteins, the immunophilins. This tight complex is proposed as the biologically active moiety that interacts with intracellular molecules involved in signal transduction.It inhibits phosphatase activity of calcineurin, an action that may impair the generation and/or activation of nuclear transcription factors required for lymphokine (particularly interleukin-2) gene expression. Tacrolimus has also been reported to have potential in multiple sclerosis, psoriasis, rheumatoid arthritis and uveitis associated with Behcet‘s disease.
Verwenden
FK-506 (Tacrolimus) is a macrolide immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system