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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

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
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
transplant matching system
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

following transplantation
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.
preventing transplant rejection
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
preventing transplant rejection1
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
uses for tacrolimus
Uses for Tacrolimus
  • Dermatitis, pruritus and psoriasis
  • Systemic lupus erythematosus
  • Organ transplants and allograft
  • Management of severe autoimmune diseases
slide8

Structure of Tacrolimus

http://www.drugbank.ca/drugs/DB00864

drug classes of tacrolimus
Drug Classes of Tacrolimus

Tacrolimus is derived from the bacteria Streptomyces tsukubaensis

Drug class:

  • Antipsoriatic
  • Immune suppressant: Calcineurin inhibitor
metabolism
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)
adverse events
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

summary
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
references
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