No 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.

The effects of in vitro carbamylation of plasma with potassium cyanate on drug-protein binding have been investigated. Potassium cyanate added to samples of normal plasma and incubated for 30 to 150 min induced time-related plasma protein carbamylation. Carbamylation of plasma did not influence quinidine protein binding, but resulted in decreased salicylate binding. The increased free fraction of salicylate in plasma correlated with the degree of carbamylation of plasma proteins (r = 0.99; p less than 0.001). Plasma from patients with chronic renal disease showed varying degrees of plasma protein carbamylation, correlating with the values of free plasma salicylate (r = 0.80; p less than 0.05). Scatchard plots for sulfadiazine binding in plasma from patients with uremia and in normal plasma carbamylated in vitro with potassium cyanate showed changes in the 2 groups when compared with those in normal individuals. If cyanate is produced in vivo from urea in patients with uremia, plasma protein carbamylation may play a role in the decreased plasma protein binding of some acidic drugs.

Fractional hydrolysis and acetylation of procainamide, acetylation of procainamide-derived p-aminobenzoic acid and plasma hydrolysis of procaine were studied in 20 patients with chronic heart failure (CHF), 20 patients with chronic respiratory insufficiency (CRI) and 20 patients with chronic renal failure (RF). The results were compared with those obtained in a group of 20 normal volunteers. Hydrolysis of procainamide and procaine were reduced in patients with CHF and CRI, but not in patients with RF. Moreover, more marked decreases in procainamide and procaine hydrolysis were seen in subgroups with secondary hepatic dysfunction. The diminution of hydrolysis of procainamide was not paralleled by changes in acetylation of procainamide or p-aminobenzoic acid. It is concluded that in patients with hepatic involvement secondary to advanced CHF or CRI, hepatic and plasmatic hydrolysis activity is decreased to a degree equivalent to primary liver failure.