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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“…Protein binding strongly influences a drug's distribution and/or clearance, and a number of studies have illustrated altered protein binding in patients with type II diabetes and hyperlipidemia (47)(48)(49). Lipids are known to interact directly with proteins to alter their capacity for drug binding via competitive or allosteric modulation.…”

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“…Discovery of glucose dependent chemical modification of various proteins suggested that they could induce functional abnormalities, and thereby lead to the pathophysiology of diabetes [27]. Glycation of albumin changes its binding to drugs and its kidney transport [28]. Lens crystalline in diabetic patients undergo glycation reaction leading to the formation of high molecular weight mass that causes turbidity in lenses [29].…”

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“…has been shown to alter the binding of acidic drugs to site I on albumin [42][43][44], In adult patients with DM, Ruiz-Cabello and Erill [11] have demonstrated altered binding of the site I-specific drug sulfisoxazole and nor mal binding of the site II-specific drug diaz epam. These authors also demonstrated a linear relationship between the extent of glycation of circulating serum proteins and the extent (%) of free sulfisoxazole, and no rela tionship between gly-Hgb (%) and the sulfisoxazole-free fraction [11], They concluded that the serum protein binding of acidic drugs may be altered in patients with DM.…”

“…Ruiz-Cabello and Erill [11] have dem onstrated that increased serum concentra tions of glycated proteins altered the binding of a weak acid, sulfisoxazole, in adults with type II DM. These authors also demon strated a correlation between the free frac tion of sulfisoxazole and the extent of glyca tion of serum proteins, a finding suggestive of a direct relationship between glycémie…”

“…Diabetes can alter the serum protein binding of drugs by two mechanisms: in creased diffusion of serum proteins to the interstitial compartment [6] and by nonen zymatic glycation of circulating proteins [11]. Ruiz-Cabello and Erill [11] have dem onstrated that increased serum concentra tions of glycated proteins altered the binding of a weak acid, sulfisoxazole, in adults with type II DM.…”