Drug Interaction Between Cyclosporine and mTOR Inhibitors in Experimental Model of Chronic Cyclosporine Nephrotoxicity and Pancreatic Islet Dysfunction

It is known that sirolimus (SRL) aggravates cyclosporine A (CsA)-induced nephrotoxicity and pancreatic injury, but the influence of everolimus (EVR) on CsA-induced organ injury is undetermined. Rats were treated with CsA (15 mg/kg) and EVR or SRL (0.3 mg/kg) subcutaneously for 4 weeks. The influences of EVR or SRL on CsA-induced nephrotoxicity and pancreatic islet dysfunction were compared, and drug interactions between CsA and EVR or SRL were evaluated at blood and tissue levels. Treatment with EVR or SRL alone did not cause severe pancreatic dysfunction and renal injury, but when combined with CsA they aggravated CsA-induced pancreatic and renal injury. Drug interactions between CsA and EVR or SRL differed at the tissue level. Combined treatment with CsA and SRL significantly increased the CsA or SRL levels in kidney and pancreas compared with CsA or SRL alone. However, combined treatment with CsA and EVR did not increase CsA or EVR levels in kidney and pancreas. Both EVR and SRL aggravate CsA-induced organ injury, but the pharmacologic interaction between EVR and CsA at the tissue level is less than that between CsA and SRL. This finding provides better understanding of the difference between EVR and SRL when combined with CsA treatment.