ORAL-ADMINISTRATION OF RAPAMYCIN AND CYCLOSPORINE DIFFERENTIALLY ALTER INTESTINAL FUNCTION IN RABBITS

The immunosuppressive drugs rapamycin (Rap) and cyclosporine A (CsA) a re used clinically to modify or abolish immune-mediated functions. Thi s study examined the effect of orally administered regimens of Rap, Cs A, and a combination of Rap/CsA on intestinal function in male New Zea land white rabbits. Animals received oral doses of CsA (15 mg/kg/body weight/day), low-dose (LD) and high-dose (HD) Rap (0.25 or 1 mg/kg/bod y wt/day, respectively), or Rap/CsA (0.25 and 5 mg/kg/body wt/day, or 0.5 and 5 mg/kg/body wt/day, respectively) for 20 days. We measured in vitro uptake of nutrients and permeability, and morphometric measurem ents in the jejunum and ileum were made. Animals receiving; HD-Rap or HD-Rap/CsA had decreased food intake, body weight, and intestinal weig ht, when compared with LD-Rap, LD-Rap/CsA, CsA, or controls. The maxim al transport rate (V-max) for the active jejunal uptake of D-glucose w as increased in HD-Rap and CsA, but not in the HD-Rap/CsA-treated anim als. The jejunal V-max of D-glucose in the LD-Rap- or -Rap/CsA-treated animals was no different from controls. In the HD-Rap- and HD-Rap/ Cs A-treated animals, jejunal rates of uptake of stearic, linoleic, and l inolenic acids were reduced when compared with controls. Jejunal and i leal permeability las assessed by the passive uptake of L-glucose, tis sue conductance, and mucosal-to-serosal flux of [H-3]inulin) was incre ased in animals treated with HD-Rap or HD-Rap/CsA, when compared with CsA or controls. These parameters of permeability were no different at lower doses of Rap or Rap/CsA, The jejunal and ileal villous surface area was increased in CsA, but decreased in HD-Rap or HD-Rap/CsA anima ls. Thus, HD-Rap given alone or in combination with CsA reduced body w eight gain, in part due to reduced food intake and malabsorption of li pids, which was due at least in part to reduced intestinal surface are a, The relevance of these findings to patients undergoing chronic immu nosuppressive drug therapy needs to be established.