Effect of combined immunosuppressive drug therapy on small intestinal nutrient transport in the rat

Objective: Prevention of rejection and preservation of graft function remai n as obstacles to clinical small intestinal transplantation (SIT). This stu dy evaluated the effects of combined immunosuppressive agents (FK506, Rapam ycin, and Mycophenolate Mofetil) an intestinal function and animal well bei ng. Methods: Screening for additive toxicity was done in experiment one (D1, n = 10); doses were: FK506 0.3 mg/kg/d, Rapamycin 2 mg/kg/d, and Mycophenolat e Mofetil 20 mg/kg/d, orally once daily. Control animals (C1, n = 10) recei ved equivalent vehicle. in the second phase of the experiment, the effect o f an additional parenteral treatment phase was investigated, with drug trea ted animals (D2, n = 6) received FK506 0.3 mg/kg, Rapamycin 1 mg/kg, and My cophenolate Mofetil 10 mg/kg so q12h for 1 week followed by FK506 3 mg/kg, Rapamycin 1 mg/kg, and Mycophenolate Mofetil 10 mg/kg po q12h for 4 weeks. Control animals (C2, n = 6) received equivalent vehicle. Parameters followe d were weight gain, nutrient absorption, drug levels and nutrient transport in vitro. Results: Controls grew normally, while weight gain was significantly reduce d in drug treated animals: This was paralleled by a reduction in dietary fa t absorption. Drug levels were low to therapeutic for all drugs in both exp eriments; FK506 appeared to affect Rapamycin and Mycophenolate Mofetil meta bolism, increasing levels of both as FK506 doses increased. Nutrient transp ort was either not effected (D1) or increased (D2). Conclusions: We conclude that low dose combination immunosuppressive therap y inhibits weight gain, without affecting absorption of dietary energy, or adversely affecting glucose transport. We postulate a systemic metabolic ca use, which requires additional investigation at the cellular level; additio nal studies are also required to determine if the additive immunosuppressio n outweigh the side effects for SIT. Copyright (C) 1999 The Canadian Societ y of Clinical Chemists.