Differentiated effects of liver cirrhosis on the albumin binding sites for diazepam, salicylic acid and warfarin

The protein binding of diazepam, salicylic acid and warfarin in serum of patients with liver cirrhosis has been studied by equilibrium dialysis and circular dichroism measurements and compared with that in normal serum. Diazepam and warfarin are mainly bound to two separate sites on the serum albumin molecule and salicylic acid to both sites. The binding of diazepam and salicylic acid was impaired in serum from the patients when compared with the binding in serum from healthy individuals, while the binding of warfarin was unchanged. The results were the same when the binding was studied with albumin isolated from patient serum and normal serum. After treatment of the albumin with charcoal at pH 3, however, the binding was improved. The apparent binding constants of the drugs in serum both from patients with liver cirrhosis and from healthy persons were increased by dilution of the sera in buffer. This effect is due to the presence of competitive inhibitors in the sera. The decreased binding of diazepam and salicylic acid in the serum from the patients with liver cirrhosis can in addition be related to the presence of allosteric inhibitors specifically affecting the diazepam binding site on albumin, while the warfarin site apparently is unaffected.