Editing Tacrolimus (section)

==Pharmacology==
===Mechanism of action===
[[File:PDB 1fkk EBI.jpg|thumb|[[FKBP12]], the target protein of tacrolimus]]
Tacrolimus is a [[macrolide]] [[calcineurin inhibitor]]. In [[T cells]], activation of the T cell receptor normally increases intracellular calcium, which acts via [[calmodulin]] to activate [[calcineurin]]. Calcineurin then dephosphorylates the transcription factor [[NFAT|nuclear factor of activated T cells]] (NF-AT), which moves to the nucleus of the T cell and increases the activity of genes coding for IL-2 and related cytokines. Tacrolimus prevents the dephosphorylation of NF-AT.<ref>{{cite book| vauthors = Ganong WF |title= Review of medical physiology|edition=22nd |publisher=Lange medical books|page=530|isbn=978-0-07-144040-0|date= 8 March 2005}}</ref>

In detail, tacrolimus reduces [[Peptidylprolyl isomerase A|peptidylprolyl isomerase]] activity by binding to the immunophilin [[FKBP12]] (FK506 binding protein), creating a new complex. This FKBP12–FK506 complex interacts with and inhibits calcineurin, thus inhibiting both T [[lymphocyte]] signal transduction and IL-2 transcription.<ref name="Cell1991-Liu">{{cite journal | vauthors = Liu J, Farmer JD, Lane WS, Friedman J, Weissman I, Schreiber SL | title = Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes | journal = Cell | volume = 66 | issue = 4 | pages = 807–815 | date = August 1991 | pmid = 1715244 | doi = 10.1016/0092-8674(91)90124-H | s2cid = 22094672 }}</ref> Although this activity is similar to that of cyclosporin, the incidence of acute rejection is reduced by tacrolimus use over cyclosporin use.<ref name="Medscape2004-McCauley" /> 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.<ref>{{cite journal | vauthors = Abou-Jaoude MM, Najm R, Shaheen J, Nawfal N, Abboud S, Alhabash M, Darwish M, Mulhem A, Ojjeh A, Almawi WY | title = Tacrolimus (FK506) versus cyclosporine microemulsion (neoral) as maintenance immunosuppression therapy in kidney transplant recipients | journal = Transplantation Proceedings | volume = 37 | issue = 7 | pages = 3025–3028 | date = September 2005 | pmid = 16213293 | doi = 10.1016/j.transproceed.2005.08.040 }}</ref>

===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 [[Cmax (pharmacology)|highest blood plasma concentrations]] (C<sub>max</sub>) 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 [[erythrocyte]]s; only 5% are found in the [[blood plasma|plasma]], of which more than 98.8% are bound to [[plasma protein]]s.<ref name="AC" /><ref name="Dinnendahl">{{cite book|title=Arzneistoff-Profile|editor1=Dinnendahl, V |editor2=Fricke, U |publisher=Govi Pharmazeutischer Verlag|location=Eschborn, Germany|date=2003|edition=18|volume=9|isbn=978-3-7741-9846-3|language=de}}</ref>

The substance is metabolized in the liver, mainly via [[CYP3A]], and in the intestinal wall. All [[metabolite]]s 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 (pharmacology)|clearance]]. Tacrolimus is predominantly eliminated via the faeces in form of its metabolites.<ref name="AC" /><ref name="Dinnendahl" />

When applied locally on eczema, tacrolimus has little to no bioavailability.<ref name="AC" />

===Pharmacogenetics===
The predominant enzyme responsible for metabolism of tacrolimus is [[CYP3A5]]. [[Genetic variation]]s within ''CYP3A5'' that result in changes to the activity of the CYP3A5 protein can affect concentrations of tacrolimus within the body. In particular, individuals who are [[homozygous]] for the G [[allele]] at the [[single nucleotide polymorphism]] (SNP) rs776746 (also known as CYP3A5 *3/*3) have a non-functional CYP3A5 protein. The frequency of the G allele varies worldwide, from 4% in some African populations to 80–90% in Caucasian populations.<ref name="Bains2012">{{cite web| vauthors = Bains RK |title=Molecular diversity and population structure at the CYP3A5 gene in Africa|url=http://discovery.ucl.ac.uk/1356293/7/1356293_R%20Bains%20ELECTRONIC%20VERSION%20thesis%20-%20post%20viva.pdf|publisher=University College London|access-date=13 June 2016}}</ref> Across a large number of studies, individuals homozygous for the G allele have been shown to have higher concentrations of tacrolimus and require lower doses of the drug, as compared to individuals who are not homozygous for the G allele. Achieving target concentrations of tacrolimus is important – if levels are too low, then there is a risk of [[transplant rejection]], if levels are too high, there is a risk of drug toxicities. There is evidence to suggest that dosing patients based on rs776746 [[genotype]] can result in faster and more frequent achievement of target tacrolimus levels. However, there is a lack of consistent evidence as to whether dosing based on rs776746 genotype results in improved clinical outcomes (such as a decreased risk for transplant rejection or drug toxicities), likely because patients taking tacrolimus are subject to [[therapeutic drug monitoring]].<ref>{{cite journal | vauthors = Staatz CE, Tett SE | title = Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation | journal = Clinical Pharmacokinetics | volume = 43 | issue = 10 | pages = 623–653 | date = 2004 | pmid = 15244495 | doi = 10.2165/00003088-200443100-00001 | s2cid = 33877550 }}</ref><ref>{{cite journal | vauthors = Staatz CE, Goodman LK, Tett SE | title = Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I | journal = Clinical Pharmacokinetics | volume = 49 | issue = 3 | pages = 141–175 | date = March 2010 | pmid = 20170205 | doi = 10.2165/11317350-000000000-00000 | s2cid = 28346861 }}</ref><ref>{{cite journal | vauthors = Staatz CE, Goodman LK, Tett SE | title = Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part II | journal = Clinical Pharmacokinetics | volume = 49 | issue = 4 | pages = 207–221 | date = April 2010 | pmid = 20214406 | doi = 10.2165/11317550-000000000-00000 | s2cid = 27047235 }}</ref><ref>{{cite journal | vauthors = Barbarino JM, Staatz CE, Venkataramanan R, Klein TE, Altman RB | title = PharmGKB summary: cyclosporine and tacrolimus pathways | journal = Pharmacogenetics and Genomics | volume = 23 | issue = 10 | pages = 563–585 | date = October 2013 | pmid = 23922006 | pmc = 4119065 | doi = 10.1097/fpc.0b013e328364db84 }}</ref>

Studies have shown that genetic polymorphisms of genes other than CYP3A5, such as NR1I2<ref>{{cite journal | vauthors = Benkali K, Prémaud A, Picard N, Rérolle JP, Toupance O, Hoizey G, Turcant A, Villemain F, Le Meur Y, Marquet P, Rousseau A | title = Tacrolimus population pharmacokinetic-pharmacogenetic analysis and Bayesian estimation in renal transplant recipients | journal = Clinical Pharmacokinetics | volume = 48 | issue = 12 | pages = 805–816 | date = 1 January 2009 | pmid = 19902988 | doi = 10.2165/11318080-000000000-00000 | s2cid = 19900291 }}</ref><ref>{{cite journal | vauthors = Choi Y, Jiang F, An H, Park HJ, Choi JH, Lee H | title = A pharmacogenomic study on the pharmacokinetics of tacrolimus in healthy subjects using the DMETTM Plus platform | journal = The Pharmacogenomics Journal | volume = 17 | issue = 1 | pages = 105–106 | date = January 2017 | pmid = 27958377 | doi = 10.1038/tpj.2016.85 | doi-access = free }}</ref> (encoding [[Pregnane X receptor|PXR]]), also significantly influence the pharmacokinetics of tacrolimus.