Correction of protein binding defect in uremic sera by charcoal treatment.

Protein binding of numerous drugs, primarily organic acids, is decreased in sera from uremic patients. The defect in binding is (1) greater than can be accounted for by hypoalbuminemia alone; (2) unchanged by prolonged in vitro dialysis; (3) transferred in the protein but not the ultrafiltrate fraction of uremic serum; and (4) not reproduced by addition of low and middle molecular weight compounds known to accumulate in uremia. However, treatment with activated charcoal at pH3 was found to significantly increase drug protein binding in uremic sera. This effect was studied with six different drugs in sera from groups of 6 normal subjects and 8 patients on chronic hemodialysis. The percentage of sulfamethoxazole, dicloxacillin, diphenylhydantoin, salicylate, and digitoxin bound to protein in normal sera (65.9, 97.1, 93.1, 96.7, and 92.7, respectively) was unchanged by charcoal treatment. In contrast, charcoal treatment significantly (p less than 0.01) increased the percentage of drug bound to protein in uremic sera from 41.7 to 59.0 for sulfamethoxazole, 90.7 to 96.3 for dicloxacillin, 84.3 to 90.8 for diphenyhydantoin, 86.4 to 93.8 for salicylate, and 89.5 to 90.9 for digitoxin. Charcoal treatment significantly (p less than 0.05) reduced penicillin protein binding in normal sera and failed to correct the binding defect for penicillin in uremic sera. The effect of charcoal can be explained by removal of an inhibitor which accumulates in uremia and (1) occupies the binding site of certain drugs, (2) changes the configuration of the albumin molecule, or (3) both. Free fatty acid (FFA) concentrations in uremic patients were similar to those in normal subjects and were not the cause of the binding defect.