Calcineurin inhibitors

• Tolypocladium inflatum: Sandos (now Novartis) told employees to bring plastic bags and collect soil samples while on vacation so that they could test it for compounds that had antibiotic activity

• soil collected from Hardanger Vidda, Norway, grew fungi. these fungi produced cyclosporine

• it was tested for antibiotic activity and found to have none; it was almost thrown away when someone from the new drug development unit decided to screen it as a new drug because it had a novel structure

• the immunosuppressive assay was positive

  • inject sheep RBC into mice

  • concurrently inject cyclosporine and look at mice antibody response. cyclosporine inhibited anti-sheep-RBC antibody production in mice

  • nothing bad happened if you injected the animals only cyclosporine and not sheep RBCs

  • however, the animals that they injected developed renal insufficiency

• Cyclosporine

  • lipid-soluble, variable absorption; microemulsion is more predictable

• Tacrolimus (FK506)

  • macrolide; well-absorbed

  • came from a bag of dirt from Mt. Tsukuba

• Mechanism of action

  • cyclosporine/tacrolimus bind to cyclophilin/FKBP, impairing ability to activate calcineurin

  • NFAT (nuclear factor of activated T cells) doesn’t get dephosphorylated, so it does not go into the nucleus to upregulate transcription

  • this is easy to use with transplantation because you know when the patient’s immune response will be turned on. it will be turned on after you transplant the graft. it is harder to use in chronic inflammation because when you intervene, the immune response is already turned on

  • markedly diminishes IL-2 production

  • augments TGF-β

• Uses

  • cyclosporine: 1980s

  • Tacrolimus: 1994

  • solid-organ transplants

  • not typically used together because of their similar mechanisms of action

• Side effects
  

  • both drugs demonstrate dose-dependent nephrotoxicity, hypertension, dyslipidemia (also caused by prednisone), glucose intolerance (also caused by prednisone), hirsutism/hyperplasia of gums

  • with tacrolimus, hirsutism/gum hyperplasia is less common and diabetes is more common

• Nephrotoxicity of calcineurin inhibitors
  

  • after 72 months, 25% of intestinal allograft recipients have chronic renal failure

  • in someone with a heart-lung transplant, you have to keep their immunosuppression very high because it can be their only hope. you can be more cavalier in kidney transplants because there is anyway always the option of dialysis

• Drug interactions
  

  • they are metabolized by CYP3A system

  • drug inhibiting this enzyme augment blood concentrations of calcineurin inhibitor

    • Ca channel blockers

    • ketoconazole

    • erythromicin

    • HIV-protease inhibitors

    • glucocorticoids

    • grapefruit juice

  • drugs inducing CYP3A can decrease blood concentrations

    • nafcillin

    • rifampin

    • phenobarbital

Category: Medical Subject Notes , Pathology Notes