Cholecystographic agents and drug binding to plasma albumin

These studies have identified two separate sites for drug binding to human serum albumin (HSA). They began in an attempt to explain the persistence in plasma of iophenoxic acid, a now abandoned oral cholecystographic agent. This is identical to iopanoic acid save for -OH instead of -NH2 in the 3 position. Iophenoxate has a half-life in man of about three years, compared to several weeks for iopanoate. Both drugs are reversibly bound to HSA with high affinity. Attempts to determine the exact extent of binding were complicated by drug-radiolysis of 125I-labeled contrast agent. Once this was overcome, reproducible data were obtained, which yielded KD at the site of highest affinity of 0.15 microM for iopanoate and 0.013 microM for iophenoxic acid, thus making the latter the most tightly bound of known drugs. We then studied competitive binding, measuring free and bound drug and competitor. From analysis by computerized programs, iophenoxate binds most firmly at site I, iopanoate most firmly at the site II, both showing competition with each other. The findings are in agreement with Sudlow, Birkett, and Wade, who identified separate binding sites with completely different techniques. They have identified a large number of commonly used drugs that bind specifically to one site or the other. It is clear that drug binding to HSA will in the future be considered in reference to specific sites. It is not known at present to what extent the cholecystographic agents may participate in drug-drug interactions related to binding to HSA. The available data will be reviewed.