Tacrolimus
[CAS# 104987-11-3]

Identification

• Classification: Biochemical >> Inhibitor >> Immune inhibitor
• Name: Tacrolimus
• Synonyms: (1R,9S,12S,13R,14S,17R,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
• Molecular Formula: C₄₄H₆₉NO₁₂
• Molecular Weight: 804.02
• CAS Registry Number: 104987-11-3
• EC Number: 658-056-2
• SMILES: C[C@@H]1C[C@@H]([C@@H]2[C@H](C[C@H]([C@@](O2)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@@H]([C@@H]([C@H](CC(=O)[C@@H](/C=C(/C1)C)CC=C)O)C)/C(=C/[C@@H]4CC[C@H]([C@@H](C4)OC)O)/C)O)C)OC)OC

Properties

• Solubility: 100 mM (ethanol), 100 mM (DMSO) (Expl.)
• Density: 1.2±0.1 g/cm³, Calc.^*
• Index of Refraction: 1.549, Calc.^*
• Boiling Point: 871.7±75.0 °C (760 mmHg), Calc.^*
• Flash Point: 481.0±37.1 °C, Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS06;GHS08 Danger
• Risk Statements: H301-H361-H372
• Safety Statements: P203-P260-P264-P270-P280-P301+P316-P318-P319-P321-P330-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	3	H301
Reproductive toxicity	Repr.	2	H361
Specific target organ toxicity - repeated exposure	STOT RE	1	H372
Acute toxicity	Acute Tox.	4	H302
Acute toxicity	Acute Tox.	3	H311
Acute toxicity	Acute Tox.	3	H331
Specific target organ toxicity - single exposure	STOT SE	3	H335
Acute toxicity	Acute Tox.	4	H332
Acute toxicity	Acute Tox.	4	H312
Skin irritation	Skin Irrit.	2	H315
Eye irritation	Eye Irrit.	2	H319
Carcinogenicity	Carc.	2	H351
Specific target organ toxicity - repeated exposure	STOT RE	2	H373

Discovery and Applications

Tacrolimus is a macrolide immunosuppressant widely used in organ transplantation and autoimmune disease management. It was first discovered in 1984 from the fermentation broth of *Streptomyces tsukubaensis*, a soil bacterium isolated in Tsukuba, Japan. Researchers were investigating microbial metabolites with immunosuppressive properties, leading to the identification of tacrolimus as a potent inhibitor of T-cell activation. This discovery marked a significant advancement in transplant medicine, providing an alternative to cyclosporine with improved efficacy and reduced toxicity in certain cases.

The primary application of tacrolimus is in preventing organ rejection in kidney, liver, and heart transplant recipients. It acts by binding to the FK506-binding protein (FKBP-12), forming a complex that inhibits calcineurin, a key enzyme in T-cell activation. This mechanism suppresses the immune response, reducing the risk of graft rejection. Compared to cyclosporine, tacrolimus offers a more selective immunosuppressive profile and is associated with a lower incidence of chronic rejection.

Beyond transplantation, tacrolimus has gained prominence in the treatment of autoimmune diseases, particularly in dermatology. It is formulated as a topical ointment for managing atopic dermatitis and psoriasis, where it helps suppress inflammatory responses without the side effects of corticosteroids. Additionally, it has been explored for treating inflammatory bowel disease, systemic lupus erythematosus, and rheumatoid arthritis, demonstrating its versatility in immune modulation.

Tacrolimus has also found applications in regenerative medicine and tissue engineering. Its ability to modulate immune responses makes it valuable in stem cell transplantation and bioengineered tissue grafts. Researchers continue to investigate its potential in promoting tolerance induction, where minimal long-term immunosuppression is required for transplant recipients.

Despite its efficacy, tacrolimus requires careful therapeutic monitoring due to its narrow therapeutic window. Side effects such as nephrotoxicity, neurotoxicity, and metabolic disturbances necessitate dose adjustments based on individual patient responses. Ongoing research aims to develop new formulations and delivery methods to optimize its safety and effectiveness in clinical use.

References

1998. Topical tacrolimus for pyoderma gangrenosum. Lancet (London, England), 351(9105), 9519983.
DOI: 10.1016/s0140-6736(05)78962-5

1998. Role of calcineurin and Mpk1 in regulating the onset of mitosis in budding yeast. Nature, 392(6673), 9521328.
DOI: 10.1038/32695

2024. Immunosuppressant drugs. Reactions Weekly, 2003, 55211.
DOI: 10.1007/s40278-024-55211-6