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Abnormal serum protein binding of acidic drugs in diabetes mellitus
Abstract:
Nonenzymatic glycosylation of proteins is common in diabetes mellitus and glycosylation of serum albumin in this condition has been described. To evaluate whether glycosylation of albumin affects acidic drug binding, sulfisoxazole and diazepam binding was examined in samples of normal serum incubated with glucose and in samples of serum from 42 patients with diabetes mellitus. Incubation of normal serum with 20mM glucose for several days resulted in progressive glycosylation of proteins, with decreased binding of sulfisoxazole (100 micrograms/ml) but not of diazepam (3 micrograms/ml). Free fractions of sulfisoxazole and diazepam were higher in serum from patients with diabetes. The percentage of free sulfisoxazole in serum from 10 normal subjects was 5.1% +/- 0.2%, whereas it was 16.0% +/- 1.3% in serum from 42 patients with diabetes with varying degrees of carbohydrate control. The percentage of free diazepam in plasma was 2.6% +/- 0.1% in the normal group and 3.6% +/- 0.4% in patients with diabetes. Decreased serum albumin levels, increased levels of free fatty acids, and glycosylation of plasma proteins seem to play a role in the defective acidic drug binding in diabetes. Elevated free fatty acid levels explain the abnormal binding of diazepam and the increased free fraction of sulfisoxazole is directly related to glycosylation of plasma proteins.
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