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.