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The extent of serum protein binding of AL01576, phenytoin (DPH), diazepam (DIAZ), and propranolol (PRO) was evaluated in a group of nondiabetic and a group of insulin-dependent diabetic subjects, as well as in streptozotocin-treated rats. Both serum glucose and glucosylated protein levels were elevated in the diabetic patient population (179 and 150% of control values, respectively). The mean free fractions (f p) of AL01576, DPH, and PRO were not statistically different for the two human groups. The DIAZ f p was slightly elevated (P < 0.05) in the diabetic patients (mean = 0.016) compared to the control group (mean f p = 0.014). An acute ( 20 days) diabetic rodent model was evaluated using Sprague–Dawley rats following streptozotocin administration (60 mg/kg i.p.). Both diabetic rat groups exhibited substantial increases in serum glucose, free fatty acids (FFA), and protein glucosylation compared to controls. The f p of AL01576 was increased in both the acute (mean = 0.248) and the chronic (mean = 0.202) condition compared to controls (mean = 0.163). The f p of DPH was also markedly increased in the acute (mean = 0.348) and the chronic (mean = 0.280) models compared to untreated controls (mean = 0.207). DIAZ and PRO binding was largely unaffected by the streptozotocin treatment. In vitro studies of purified human albumin suggest that a considerable degree of glucosylation would need to be present in diabetic serum before it would effectively alter drug binding. Our data suggest that only minor drug–serum binding changes occur in diabetic patients who are otherwise healthy and whose disease is well controlled.