Tacroz/Tacroz Forte Mechanism of Action

Pharmacology: Pharmacodynamics: The exact mechanism of action of tacrolimus 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 effect has been shown to prevent 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 (such as interleukin-2, gamma interferon). Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-(alpha), 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 down regulate the expression of Fc[erg]RI on Langerhans cells.
Pharmacokinetics: Systemic absorption with topical Tacrolimus is minimal. After single or multiple doses of 0.1% Tacrolimus Ointment, peak tacrolimus blood concentrations ranged from undetectable to 20 ng/mL. The results from a pharmacokinetic study of 0.1% Tacrolimus Ointment in 20 pediatric atopic dermatitis patients (ages 6-13 years), show peak tacrolimus blood concentrations below 1.6 ng/mL in all patients.
The absolute bioavailability of topical tacrolimus is unknown. Using intravenous historical data for comparison, the bioavailability of tacrolimus from Tacrolimus Ointment in atopic dermatitis patients is less than 0.5%. In adults with an average of 53% BSA treated, exposure (i.e., AUC) of tacrolimus is approximately 30-fold less than that seen with oral immunosuppressive doses in kidney and liver transplant patients. The lowest tacrolimus blood level at which systemic effects can be observed is not known. There was no evidence based on blood concentrations that tacrolimus accumulates systemically upon intermittent topical application for periods of up to 1 year.