Mammalian Target of Rapamycin Inhibitor

Aka: Mammalian Target of Rapamycin Inhibitor, mTOR Inhibitor, Temsirolimus, Torisel

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II. Indications

  1. Solid Organ Transplant Immunosuppression (maintenance prevention of rejection)
  2. Tuburous Sclerosis
  3. Cancer
    1. Renal Cell Carcinoma
  4. Ongoing research into mTOR Inhibitors as anti-aging drugs
    1. Resources
      1. Rapamycin (Peter Attia, Drive)
        1. https://peterattiamd.com/davidsabatini-mattkaeberlein/
    2. References
      1. Blagosklonny (2019) Aging 11(19):8048-67 +PMID: 31586989 [PubMed]
      2. Juricic (2022) Nat Aging 2(9):824-36 +PMID: 37118497 [PubMed]
      3. Lee (2024) Lancet Healthy Longev 5(2):e152-e162 +PMID: 38310895 [PubMed]

III. Mechanism

  1. Mammalian Target of Rapamycin Pathway (mTOR Pathway)
    1. Mammalian Target of RapamycinProtein (mTOR Protein)
      1. Serine-Threonine Kinase composed of a Protein complex (5-6 components) with 2 types (mTOR1, mTOR2)
      2. Regulates Protein synthesis in response to cellular stress
      3. Part of the PI3K/AKT pathway
    2. mTOR has multiple associated triggers in pathophysiology
      1. Cancer formation and Angiogenesis
      2. Insulin Resistance and Diabetes Mellitus
      3. Adipogenesis
      4. T-Lymphocyte activation
  2. mTOR Inhibitors
    1. Rapamycin (a Macrolide), and its analogs bind and inhibit mTOR
    2. Block the Serine-Threonine kinase receptor signaling
    3. Inhibit mRNA expression related to Cell Cycle progression and arrest cell in G1 phase

IV. Medications

  1. Sirolimus (Rapamune, Rapamycin)
  2. Everolimus (Afinitor, Zortress)
  3. Temsirolimus (Torisel)

V. Adverse Effects

  1. Nephrotoxicity including Proteinuria
  2. Myelosuppression
  3. Rash
  4. Delayed Wound Healing
  5. Secondary Malignancy (including Lymphoma)
  6. Male Infertility
  7. Cardiopulmonary
    1. Interstitial Lung Disease or Pulmonary fibrosis
    2. Hyperlipidemia
    3. Edema
    4. Thrombosis
      1. Hepatic artery thrombosis
      2. Kidney graft thrombosis
  8. Thrombotic Thrombocytopenic Purpura (TTP) or Hemolytic Uremic Syndrome (HUS)
    1. More common in combination with Cyclosporine
  9. Angioedema
    1. More common in combination with ACE Inhibitors
  10. Serious Infections (including Polyoma Virus Infections)
    1. Latent Viral Infection activation
    2. BK virus associated nephropathy

VI. Drug Interactions

  1. See Cytochrome P-450 3A4
  2. Many Drug Interactions related to CYP3A4
  3. Agents that increase Purine Synthesis Inhibitor concentrations
    1. Linezolid potentiates myelosuppression
    2. Erythromycin (and Clarithromycin to a lesser extent)
  4. Agents that decrease Purine Synthesis Inhibitor concentrations
    1. Rifampin

VII. Resources

  1. Sirolimus (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2e6130e5-fa94-dcf8-605c-817bf396e93d
  2. Everolimus (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=45d54974-3fc4-4237-a2fa-3158ca1a8105
  3. Temsirolimus (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=95b7dc92-2180-42f1-8699-3c28f609e674

VIII. References

  1. Cimino (2016) Am Fam Physician 93(3): 203-10 [PubMed]
  2. Costanzo (2010) J Heart Lung Transplant 29(8): 914-56 [PubMed]

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