In vitro: Tacrolimus (FK506) inhibits calcium-dependent events, such as IL-2 gene transcription, NO synthase activation, cell degranulation, and apoptosis. Tacrolimus also potentiates the actions of glucocorticoids and progesterone by binding to FKBPs contained within the hormone receptor complex, preventing degradation. The agent may enhance expression of the TGFβ-1 gene in a fashion analogous to that demonstrated for CsA. T cell proliferation in response to ligation of the T cell receptor is inhibited by Tacrolimus. Tacrolimus (FK506) is a powerful immunosuppressive drug widely used to prevent organ rejection after transplantation. Tacrolimus inhibit other calcineurin-dependent transcription factors including the ubiquitously expressed cAMP response element-binding protein (CREB). Tacrolimus inhibit CREB transcriptional activity at the coactivator level. The depolarization-induced transcriptional activity of the CBP C-terminus is enhanced by overexpression of calcineurin and is inhibited by Tacrolimus in a concentration-dependent manner with IC50 of 1 nM consistent with IC50 for inhibition of calcineurin.
In vivo: In the pleurisy induced by carrageenan, Tacrolimus (1 mg/kg, i.p.) and Dexamethasone (0.5 mg/kg, i.p.) administered 0.5 h before causes a significant decrease in leukocytes, neutrophils and exudation (P<0.01). Under the same conditions, Tacrolimus and Dexamethasone do not modify the blood's white or red cells (P>0.05). Tacrolimus shows a long lasting antiinflammatory effect, inhibiting leukocytes and neutrophils for up to 24 h (P<0.01), whereas the inhibition of exudation is less marked (up to 2 h) (P<0.01). These drugs caused a marked reduction in MPO activity, as well as IL-1β and TNFα levels (P<0.01), but only Tacrolimus inhibits ADA activity (P<0.01). Tacrolimus significantly inhibits cell migration induces by either bradykinin, histamine or substance P (P<0.05).
|Animal models||Swiss mice|
|Formulation||sterile saline (NaCl 0.9%)|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||10 mM in DMSO|
Tacrolimus pharmacodynamics and pharmacogenetics along the calcineurin pathway in human lymphocytes.
Noceti OM, et al. Clin Chem. 2014 Oct;60(10):1336-45. PMID: 25142246.
Olmesartan attenuates tacrolimus-induced biochemical and ultrastructural changes in rat kidney tissue.
Al-Harbi NO, et al. Biomed Res Int. 2014;2014:607246. PMID: 24987695.
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