Cilastatin-insulin interaction in the rat.

The administration of the selective renal dehydropeptidase I inhibitor cilastatin on insulin pharmacokinetics and pharmacodynamics was studied in the intact rat model. After either a single iv dose of cilastatin, 25 mg/kg, or saline, a 30-min urine sample and pre- and postcollection blood samples were obtained from rats infused to steady state with either saline or insulin. There were no significant changes in insulin or glucose handling in groups administered saline with or without cilastatin. In rats with elevated serum insulin concentrations (greater than 75 microU/ml), cilastatin produced a 2-fold decrease in fractional urinary clearance of insulin (1.03 +/- 0.49 vs. 2.30 +/- 0.72%; p = 0.0026). No differences in renal function as assessed by creatinine clearance and sodium transport were observed between the groups. Serum glucose levels decreased by 46% and were significantly correlated with serum insulin levels (r = -0.66; p = 0.003). The administration of cilastatin to a patient exhibiting hyperinsulinemia may decrease the total body clearance of insulin resulting in profound hypoglycemia.