Pharmacotherapeutic Group: Immunosuppressive agent.
Pharmacology: Mechanism of Action: Tacrolimus inhibits T-lymphocyte activation although the exact mechanism of action is not known. Experimental evidence suggests that tacrolimus binds 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 inhibited. This effect may 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 (eg, interleukin-2, γ interferon). The net result is the inhibition of T-lymphocyte activation (ie, immunosuppression).
Pharmacokinetics: Due to intersubject variability in tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability of tacrolimus is 97.62%; its maximum blood concentration (Cmax) is 21.66 ng/mL and area under the curve (AUC0-t) is 146.46 ng·hr/mL and AUC0-inf is 259.08 ng·hr/mL. Tmax is 3.5 hrs and t½ is 13.21 hrs. The rate and the extent of tacrolimus absorption is greatest under fasted conditions. The plasma protein-binding of tacrolimus is approximately 99%. Tacrolimus is bound mainly to albumin and α1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors eg, hematocrit, temperature at the time of plasma separation, drug concentration and plasma protein concentration. Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-dimethyl tacrolimus.