Original Article Calcineurin inhibitors suppress intestinal cellular respiration

The calcineurin inhibitors, tacrolimus and cyclosporine, are commonly used immunosuppressants, and transplant patients on these medications often develop gastrointestinal symptoms. This in vitro study investigated their effects on intestinal cellular respiration (the process of delivering nutrients and O 2 to the mitochondria, oxida- tion of reduced metabolic fuels, passage of electrons to O 2 , and synthesis of ATP) in C57BL/6 mice. For this purpose, a phosphorescence analyzer was used to measure cellular mitochondrial O 2 consumption (k c , µM O 2 min -1 mg -1 ) in fragments from the small intestine in the presence of 10 µM drug or 1.6 µL dimethyl-sulfoxide (drug vehicle). Tacrolimus and cyclosporine significantly reduced the rate of intestinal cellular respiration by 28% and 35%, re - spectively. Cyclosporine had no effects on cellular respiration in renal tissue. Intestinal respiration was unaffected by the multikinase inhibitors sorafenib and regorafenib, the mTOR inhibitors sirolimus and everolimus, the PI3K/ mTOR inhibitors BEZ235, GDC0980 and GSK2126458, the MEK inhibitor GSK1120212, and the P110δ inhibitor idelalisib. Thus, calcineurin inhibitors specifically impair intestinal cellular respiration. The mechanism and clinical significance of this in vitro event require further studies.