Interaction of cyclosporine and indomethacin in the rat

The renal toxicity of cyclosporine has been reported to be due, at least in part, to a decrease in renal blood flow. Inasmuch as nonsteroidal antiinflammatory compounds also decrease renal blood flow, cyclosporine and such an agent (indomethacin) were given together to determine if there was an interaction in the kidney. Rats, 250-300 g, were divided into 4 groups: control, indomethacin (5 mg/kg), cyclosporine (25 mg/kg) and cyclosporine + indomethacin. At weekly intervals, renal excretion of creatinine/24 hrs and N-acetyl-beta-D-glucosaminidase activity in urine (NAG) were determined as well as body weights. At one week, values for creatinine, NAG and weight did not differ between the groups. At two weeks, the animals in the cyclosporine + indomethacin group showed decreased creatinine excretion and increased NAG excretion. At three weeks, 90% of the animals in the cyclosporine + indomethacin group were dead. Thus, when indomethacin and cyclosporine are given together, they interact to produce an increase in renal toxicity and lethality.