Cyclosporine toxicity in rabbits

Rabbits treated with an immunosuppressive dose of cyclosporine for a prolonged period of time developed a clinically distinct toxic syndrome characterized by wasting, loss of weight, reduced food and water consumption and reduced movement. Ultimately 74 of 153 animals died within 60 days of treatment with a distended stomach and intestines full of dry undigested food. The syndrome was dose dependent but seemed unrelated to the route of administration. It occurred in two strains and two different colonies. No infectious agent was implicated. Histological examination and a variety of laboratory tests did not elucidate the syndrome. It could not be prevented by drugs that increased bowel movement or gastric emptying and was more pronounced in animals given additional indomethacin. Reduction of cyclosporine dose reduced toxicity but at the expense of reduced immunosuppression. We were unable to define a therapeutic non-toxic range by serial determination of cyclosporine blood concentrations. This highlights the difficulty in obtaining a therapeutic dosage level in rabbits on long-term cyclosporine immunosuppression.