calcineurin; anti-inflammatory

Pimecrolimus (SDZ-ASM 981) (100 nM) selectively acts on cells that are essential for the effector phase of an inflammatory reaction, specifically targeting T-cells and mast cells. It inhibits the production and release of cytokines and other inflammatory mediators, as well as the expression of signals necessary for the activation of inflammatory T-lymphocytes[1]. In both murine and human mixed lymphocyte reactions, cipecrolimus (10 nM; 3 days) reduces the polyclonal development of peripheral blood T cells[2]. after antigen-specific stimulation, inhibits the production of cytokines IL-2, IL-4, IL-10, and interferon-γ from T-cell clone CFTS4:3.1 with IC50s of 0.28, 0.3, 0.2, and 0.42 nM, respectively[2].

In mice and pigs, pimecrolimus (SDZ-ASM 981) (0-0.4%; topical; 10 μL once) prevents allergic contact dermatitis[3]. In mice and rats, dipecrolimus (0-90 mg/kg; po or sc; twice or once) significantly reduces allergic contact dermatitis[3].

Cell Proliferation Assay[2]
Cell Types: T-cell clone (TCC), murine and human mixed lymphocyte reactions (MLR)
Tested Concentrations: 0-10 nM
Incubation Duration: 3 days
Experimental Results: Inhibited proliferation of TCC CFTS 4:3.1 with IC50s of 0.78- 2.6 nM. Inhibited murine and human MLR with IC50s of both 1.3 nM.

Animal/Disease Models: Female NMRl mice, allergic contact dermatitis model[3]
Doses: 0.004%, 0.01%, 0.04%, 0.13% and 0.4% in10 μL ethanolic solution
Route of Administration: Topical application, once
Experimental Results: Inhibited oedema formation by 17% at concentration of 0.004%.

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Animal/Disease Models: Female NMRl mice, allergic contact dermatitis model[3]
Doses: 10, 30, 90 mg/kg (oral) or 1.5, 4.5, 13.5 mg/ kg (subcutaneous)
Route of Administration: Oral (twice) or subcutaneous (sc) administration (once)
Experimental Results: Signiticantiy inhibited inflammatory ear oedema formation.

Absorption, Distribution and Excretion
Because of the low systemic absorption of pimecrolimus following topical application the calculation of standard pharmacokinetic measures such as AUC, Cmax, half-life, etc. cannot be reliably done.
80% of the drug is excreted in the feces.

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Metabolism / Metabolites
No drug metabolism was observed in human skin in vitro. Oral administration yielded metabolites produced from O-demethylation and oxygenation reactions.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Topical pimecrolimus has not been studied during breastfeeding; however, it is used topically in children as young as 3 months of age. Because it is poorly absorbed after topical application and plasma concentrations after topical use in adults are less than 2 mcg/L, it is a low risk to the nursing infant. Ensure that the infant's skin does not come into direct contact with the areas of skin that have been treated. Current guidelines allow topical pimecrolimus to be applied to the nipples just after nursing for eczema, with the nipples cleaned gently before nursing.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
74%-87% (in vitro, bound to plasma proteins)

[1]. Pimecrolimus -- an anti-inflammatory drug targeting the skin. Exp Dermatol. 2004 Dec;13(12):721-30.

[2]. A novel anti-inflammatory drug, SDZ ASM 981, for the treatment of skin diseases: in vitro pharmacology. Br J Dermatol. 1999 Aug;141(2):264-73.

[3]. A novel anti-inflammatory drug, SDZ ASM 981, for the topical and oral treatment of skin diseases: in vivo pharmacology. Br J Dermatol. 1997 Oct;137(4):568-76.

Pimecrolimus is a lactam and a macrolide.
Pimecrolimus is an immunomodulating agent that was first marketed by Novartis under the trade name Elidel. It is now promoted in Canada by Galderma since early 2007. It is currently available as a topic cream used in the treatment of atopic dermatitis (eczema).
Pimecrolimus is a Calcineurin Inhibitor Immunosuppressant. The mechanism of action of pimecrolimus is as a Calcineurin Inhibitor.
Pimecrolimus is a 33-epi-chloro-derivative of the ascomycin macrolactam with immunosuppressant property. Pimecrolimus binds to the receptor macrophilin-12 (FKBP-12) forming a complex that blocks the calcium-dependent signal transduction cascade mediated by calcineurin. Via dephosphorylation, calcineurin is the enzyme responsible for activating nuclear factor of activated T-cells (NF-AT), a T cell transcriptional regulatory factor. As a consequence, the synthesis and release of Th1- (T helper 1) and Th2- (T helper 2) type cytokines, and other inflammatory mediators from T-cells and mast cells are blocked and the expression of signals essential for the activation of inflammatory T-lymphocytes is inhibited. However, pimecrolimus mode of action is cell-selective and does not affect Langerhans' cells/dendritic cells and primary fibroblasts.

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Drug Indication
For treatment of mild to moderate atopic dermatitis.
FDA Label

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Mechanism of Action
Pimecrolimus binds with high affinity to macrophilin-12 (FKBP-12) and inhibits the calcium-dependent phosphatase, calcineurin. As a consequence, it inhibits T cell activation by blocking the transcription of early cytokines. In particular, pimecrolimus inhibits at nanomolar concentrations Interleukin-2 and interferon gamma (Th1-type) and Interleukin-4 and Interleukin-10 (Th2-type) cytokine synthesis in human T cells. Also, pimecrolimus prevents the release of inflammatory cytokines and mediators from mast cells in vitro after stimulation by antigen/lgE.

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Pharmacodynamics
Pimecrolimus is a chemical that is used to treat atopic dermatitis (eczema). Atopic dermatitis is a skin condition characterized by redness, itching, scaling and inflammation of the skin. The cause of atopic dermatitis is not known; however, scientists believe that it may be due to activation of the immune system by various environmental or emotional triggers. Scientists do not know exactly how pimecrolimus reduces the manifestations of atopic dermatitis, but pimecrolimus reduces the action of T-cells and mast cells which are part of the immune system and contribute to responses of the immune system. Pimecrolimus prevents the activation of T-cells by blocking the effects of chemicals (cytokines) released by the body that stimulate T-cells. Pimecrolimus also reduces the ability of mast cells to release chemicals that promote inflammation.

C43H68CLNO11

810.45

809.448

C, 63.72; H, 8.46; Cl, 4.37; N, 1.73; O, 21.72

137071-32-0

Pimecrolimus hydrate;1000802-56-1

6509979

White to off-white solid powder

1.2±0.1 g/cm3

866.1±75.0 °C at 760 mmHg

477.6±37.1 °C

0.0±0.6 mmHg at 25°C

1.543

5.08

2

11

6

56

1440

14

Cl[C@]1([H])C([H])([H])C([H])([H])[C@@]([H])(/C(/[H])=C(\C([H])([H])[H])/[C@]2([H])[C@]([H])(C([H])([H])[H])[C@]([H])(C([H])([H])C([C@]([H])(C([H])([H])C([H])([H])[H])C([H])=C(C([H])([H])[H])C([H])([H])[C@]([H])(C([H])([H])[H])C([H])([H])[C@@]([H])([C@]3([H])[C@]([H])(C([H])([H])[C@@]([H])(C([H])([H])[H])[C@@](C(C(N4C([H])([H])C([H])([H])C([H])([H])C([H])([H])[C@@]4([H])C(=O)O2)=O)=O)(O[H])O3)OC([H])([H])[H])OC([H])([H])[H])=O)O[H])C([H])([H])[C@@]1([H])OC([H])([H])[H] |c:42|

KASDHRXLYQOAKZ-XDSKOBMDSA-N

InChI=1S/C43H68ClNO11/c1-10-30-18-24(2)17-25(3)19-36(53-8)39-37(54-9)21-27(5)43(51,56-39)40(48)41(49)45-16-12-11-13-32(45)42(50)55-38(28(6)33(46)23-34(30)47)26(4)20-29-14-15-31(44)35(22-29)52-7/h18,20,25,27-33,35-39,46,51H,10-17,19,21-23H2,1-9H3/b24-18+,26-20+/t25-,27+,28+,29-,30+,31-,32-,33-,35+,36-,37-,38+,39+,43+/m0/s1

(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(E)-1-[(1R,3R,4S)-4-chloro-3-methoxycyclohexyl]prop-1-en-2-yl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone

SDZ ASM 981; ASM-981; SDZ-ASM 981; ASM 981; SDZ-ASM-981; ASM981; ASM 981; Pimecrolimus; Pimecrolimusum; 33-epi-Chloro-33-desoxyascomycin; Brand name: Aregen; Rizan; Elidel; 137071-32-0; SDZ-ASM 981; SDZ-ASM-981; 33-epi-Chloro-33-desoxyascomycin; SDZ ASM 981; UNII-7KYV510875;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.08 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (3.08 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)