Transplantation: toxicokinetics and mechanisms of toxicity of cyclosporine and macrolides.
For over two decades, calcineurin inhibitors (CIs) have been the mainstay of immunosuppressive therapy following solid-organ transplantation. However, CI nephrotoxicity is one of the main contributors to chronic kidney allograft dysfunction. A novel class of immunosuppressants that inhibit the kinase mammalian target of rapamycin (mTOR), although not nephrotoxic themselves, enhance CI nephrotoxicity. The biochemical basis of CI toxicity and their toxicodynamic interaction with mTOR inhibitors is still poorly understood. Studies using a magnetic resonance spectroscopy-based metabonomic approach indicate that CI toxicity is caused by drug-induced mitochondrial dysfunction and that mTOR inhibitors enhance the negative effects of CIs on cell energy metabolism.
Serkova
Natalie
N
Department of Anesthesiology, Clinical Research & Development, University of Colorado Health Sciences Center, 4200 East Ninth Ave, Room UH-2122, Campus Box B113, Denver, CO 80262, USA.
Christians
Uwe
U
D000818:Animals; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000009:adverse effects / Q000737:chemistry / Q000633:toxicity*; D004347:Drug Interactions; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000737:chemistry / Q000633:toxicity*; D007700:Kinetics; D018942:Macrolides / Q000009:adverse effects / Q000737:chemistry / Q000633:toxicity*; D016377:Organ Transplantation; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D018942:Macrolides; D047428:Protein Kinase Inhibitors; D016572:Cyclosporine; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases