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Transplantation: Mechanisms of Tacrolimus

Transplantation: Mechanisms of Tacrolimus. Sarah Barnett, Jordanne Feldberg, Tamara Robinson PHM 142: October 2, 2013. PHM142 Fall 2013 Instructor: Dr. Jeffrey Henderson. Overview of Transplantation.

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Transplantation: Mechanisms of Tacrolimus

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  1. Transplantation: Mechanisms of Tacrolimus Sarah Barnett, Jordanne Feldberg, Tamara Robinson PHM 142: October 2, 2013 PHM142 Fall 2013 Instructor: Dr. Jeffrey Henderson

  2. Overview of Transplantation • Transferring cells, tissues or organs from one person (the donor) to another (the recipient) to replace the recipient’s damaged or malfunctioning one(s). • In Ontario transplanted organs can include: • small bowel, kidney, pancreas, liver, heart & lungs. • Process: • Transplant team will determine suitability for transplant • Suitable candidates who decide to move forward are placed on the waitlist • Waitlisted candidates are entered into matching system

  3. Transplant Matching System • Goal of matching system is to find an organ that will be tolerated by the recipient. • Matching occurs in 3 areas: • Blood Type Matching: ABO blood group • Tissue Type Matching: antigens • Crossmatching: identify presence of preformed antibodies  donor-recipient compatibility

  4. Following Transplantation • Immune system may still recognize the transplanted organ as foreign & lead to rejection. • Due to antigens on cell surface • Immune response consists of both cellular (lymphocyte mediated) and humoral (antibody mediated) mechanisms. • T-cells play an essential role in the rejection process • To prevent rejection patients are prescribed an immunosuppressant.

  5. Preventing Transplant Rejection • Medications suppress the immune response & prevent destruction of transplanted organ. • Must take for as long as you have the transplant (lower dose during maintenance phase) • Medications currently available: • Immunophilin-binding agents/Calcineurin inhibitors • Tacrolimus & Cyclosporine • Mammalian target of rapamycin (mTOR) inhibitors • Antiproliferative agents • Antibodies • Corticosteroids

  6. Preventing Transplant Rejection • Medications suppress the immune response & prevent destruction of transplanted organ. • Must take for as long as you have the transplant (lower dose during maintenance phase) • Medications currently available: • Immunophilin-binding agents/Calcineurin inhibitors • Tacrolimus & Cyclosporine • Mammalian target of rapamycin (mTOR) inhibitors • Antiproliferative agents • Antibodies • Corticosteroids

  7. Uses for Tacrolimus • Dermatitis, pruritus and psoriasis • Systemic lupus erythematosus • Organ transplants and allograft • Management of severe autoimmune diseases

  8. Structure of Tacrolimus http://www.drugbank.ca/drugs/DB00864

  9. Drug Classes of Tacrolimus Tacrolimus is derived from the bacteria Streptomyces tsukubaensis Drug class: • Antipsoriatic • Immune suppressant: Calcineurin inhibitor

  10. Mechanism of Normal T-cell Activation

  11. Inhibition Pathway of Tacrolimus

  12. Metabolism • Metabolized hepatically via cytochrome P450 via CYP3A • Metabolites include: 13-demethyltacrolimus and 31-O-demethyltacrolimus. Both are active • Tacrolimus excreted almost entirely as metabolites (less than 1% unchanged in urine)

  13. Adverse events Major events include: • Nephrotoxicity • GI distress • Diabetes mellitus • CNS effects (headache, tremor, confusion, insomnia) • Malignant tumors Pregnancy: it does cross the placenta; renal function must be especially monitored

  14. Summary • Donor-recipient compatibility is optimized through blood type, tissue type & crossmatching • Transplant antigens may be recognized as foreign, leading to an immune response & possibly rejection • Prevent transplant rejection by prescribing immunosuppressive drugs, such as Tacrolimus • Tacrolimus, through inhibition of Calcineurin, deactivates the immune system’s T-cells • Tacrolimus Inhibitory Mechanism • Tacrolimus (or FK506) suppresses the signal-transduction events in T-cell activation by binding to the FK Binding Protein (FKBP), forming the FK506-FKBP complex • This complex interacts with Calcineurin, preventing the dephosphorylation event of NFATc, thus blocking its entry into the nucleus • As a result, the transcription of the IL-2 gene is inhibited in the T-cells • Tacrolimus is metabolized hepatically by P450 via CYP3A. It produces active metabolites and only 1% is excreted unchanged in the urine • Adverse events including: nephrotoxicity, GI distress, CNS effects & will cross the placenta during pregnancy

  15. References Barbarino JM, StaatzCE, VenkataramananR, Klein TE, Altman RB. 2013. "Tacrolimus/Cyclosporine Pathway, Pharmacodynamics." Tacrolimus/Cyclosporine Pathway, Pharmacodynamics [PharmGKB]. Pharmacogenetics and Genomics, 2013. Web. 15 Sept. 2013. Available from: http://www.pharmgkb.org/pathway/PA165985892 Cambridge University Press. 2000. Mechanism of Action Of Cyclosporine Or Tacrolimus (FK506). Expert Reviews In Molecular Medicine, 21 June 2000. Web. 15 Sept. 2013. Available from: http://journals.cambridge.org/fulltext_content/ERM/ERM2_04/S1462399400001769sup003.pdf DrugBank. 2013. Tacrolimus. Available from: www.drugbank.ca/drugs/DBOO864 Dutta S & Ahmad Y. 2011. The Efficacy And Safety Of Tacrolimus In Rheumatoid Arthritis. Therapeutic Advances in Musculoskeletal Disease 3(6): 283-91. Print. Friedman AL & Peters T. 2006. Make Me a Perfect Match: Understanding Transplant Compatibility. Voice of the Diabetic 21(3). Available from: https://nfb.org/images/nfb/publications/vod/vod213/vodsum0601.htm Malhotra P, Malu S, Kapur S. 2013. Immunology of Transplant Rejection. Medscape. Available from: http://emedicine.medscape.com/article/432209-overview Martindale edition 36. London ; Chicago : Pharmaceutical Press, 2009 MedlinePlus. Transplant Rejection. Available from: http://www.nlm.nih.gov/medlineplus/ency/article/000815.htm Micromedex Solutions 2.0. 2013. Available from: http://www.micromedexsolutions.com/micromedex2/librarian?partner=true Royal Society of Chemistry. 2013. ChemSpider. Available from: http://www.chemspider.com/RecordView.aspx?id=393220 Schreiber SL & Crabtree GR. 1992. The Mechanism of Action of Cyclosporin A and FK506. Immunology Today 13(4): 136-42. Print. Thomson AW, Bonham CA & Zeevi A. 1995. Mode of Action of Tacrolimus (FK506): Molecular and Cellular Mechanisms. Therapeutic Drug Monitoring17(6): 584-91. Print TilneyNL, Kirkman RL, Carpenter CB, Milford EL, Lazarus JM, et.al. Chapter 12: Kidney Transplantation: A Guide for Patients. Brigham & Women’s Hospital, Boston, MA. Available from: http://msl1.mit.edu/ESD10/kidneys/HndbkHTML/ch12.htm#10 Trillium Gift of Life Network. 2013. Transplant. Available from: http://www.giftoflife.on.ca/en/transplant.htm

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