Although this activity is similar to that of cyclosporin, the incidence of acute rejection is reduced by tacrolimus use over cyclosporin use. Although short-term immunosuppression concerning patient and graft survival is found to be similar between the two drugs, tacrolimus results in a more favorable lipid profile, and this may have important long-term implications given the prognostic influence of rejection on graft survival. Pharmacokinetics
Oral tacrolimus is slowly absorbed in the gastrointestinal tract, with a total bioavailability of 20 to 25% (but with variations from 5 to 67%) and highest blood plasma concentrations (Cmax) reached after one to three hours. Taking the drug together with a meal, especially one rich in fat, slows down resorption and reduces bioavailability. In the blood, tacrolimus is mainly bound to erythrocytes; only 5% are found in the plasma, of which more than 98.8% are bound to plasma proteins.The substance is metabolized in the liver, mainly via CYP3A, and in the intestinal wall. All metabolites found in the circulation are inactive. Biological half-life varies widely and seems to be higher for healthy persons (43 hours on average) than for patients with liver transplants (12 hours) or kidney transplants (16 hours), due to differences in clearance. Tacrolimus is predominantly eliminated via the faeces in form of its metabolites.When applied locally on eczema, tacrolimus has little to no bioavailability. Pharmacogenetics
The predominant enzyme responsible for metabolism of tacrolimus is CYP3A5. Genetic variations within CYP3A5 that result in changes to the activity of the CYP3A5 protein can affect concentrations of tacrolimus within the body.
The name tacrolimus is derived from "Tsukuba macrolide immunosuppressant".Tacrolimus was first approved by the US Food and Drug Administration (FDA) in 1994, for use in liver transplantation; the indications were extended to include kidney transplants. Generic versions of tacrolimus were approved in the US in 2017.Tacrolimus was approved for medical use in the European Union in 2002, for the treatment of moderate to severe atopic dermatitis. In 2007, the indications were expanded to include the prophylaxis of transplant rejection in adult kidney or liver allograft recipients and the treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adults. In 2009, the indications were expanded to include the prophylaxis of transplant rejection in adult and paediatric, kidney, liver or heart allograft recipients and the treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adults and children. Available forms
A branded version of the drug is owned by Astellas Pharma, and is sold under the brand name Prograf, given twice daily. A number of other manufacturers hold marketing authorisation for alternative brands of the twice-daily formulation.Once-daily formulations with marketing authorisation include Advagraf (Astellas Pharma) and Envarsus (marketed as Envarsus XR in US by Veloxis Pharmaceuticals and marketed in Europe by Chiesi). These formulations are intended to reduce pharmacokinetic variation in blood levels and facilitate compliance with dosing.The topical formulation is marketed by LEO Pharma under the name Protopic. Biosynthesis
The biosynthesis of tacrolimus is hybrid synthesis of both type 1 polyketide synthases (PKS 1) and nonribosomal peptide syntheses (NRPS).