Tacrograf Mechanism of Action

Pharmacology: Pharmacodynamics: Tacrolimus suppresses cellular immunity by inhibiting T-lymphocyte activation.
Mechanism of Action: Tacrolimus binds to an intracellular protein, FKBP-12 and complexes with calcineurin dependent proteins to inhibit calcineurin phosphatase activity.
Pharmacokinetics: Absorption: Incomplete and variable; the rate and extent of absorption is decreased by food (particularly a high-fat meal). Oral absorption may be variable in stem cell transplant patients with mucositis due to the conditioning regimen. Better in resected patients with a closed stoma: unlike cyclosporine, clamping of the T-tube in liver transplant patients does not alter trough concentrations or area under the curve (AUC).
Bioavailability: Children: 7-55%; Adults: 7-32%.
Time to peak, plasma: 0.5-6 hours.
Distribution: Volume of distribution: Children: 0.5-4.7 L/kg; Adults: 0.55-2.47 L/kg.
Protein binding: Approximately 99% primarily to albumin and alpha-1-acid glycoprotein.
Metabolism: Extensively hepatic via CYP3A4 to 8 possible metabolites.
Major metabolite: 31-demethyl tacrolimus shows same activity as tacrolimus in vitro.
Excretion: Half-life elimination: variable, 23-46 hours in healthy volunteers; 2.1-36 hours in transplant patients: prolonged in patients with severe hepatic impairment.
Major excretion pathway: Feces (approximately 93%): urine (less than 1% as unchanged drug).
Special populations: Hepatic function impairment: The mean clearance was substantially lower in patients with severe hepatic impairment.
Pediatric: Children younger than 12 years need higher doses than adults to achieve similar trough concentrations.
Race: Kidney transplant patients who are black require a higher tacrolimus dose to attain trough concentrations similar to white patients.