PARTICULATE CONTRAST AGENTS. CHARACTERIZATION OF ALBUMIN BINDING TO IODIPAMIDE ETHYL ESTER AND ITS EFFECT ON EFFICACY AND TOXICITY

Abstract

The selective uptake and longer retention of a radiopaque particulate suspension by reticuloendothelial cells provide definite advantages over water-soluble urographic agents in hepatic CT scanning. The major concern with using particulate contrast agents has been the relatively high acute toxicity or the indefinite retention of the agent in the organism. The purpose of this paper is to characterize the albumin binding to one such agent, iodipamide ethyl ester (IDE), which is known to be cleared from the rat liver within 2–3 days, and to demonstrate the importance of preincubation of this agent in albumin prior to injection. Using 125I-labelled human serum albumin (HSA) we have defined the moles of HSA binding to each mole of IDE as a function of the incubation molar ratio. More than 95% of HSA bound to IDE is retained after repeated washings with normal saline. In vitro incubation of HSA-coated IDE in human plasma results in gradual decrease of radioactivity associated with the particles; at 10 minutes into the incubation, corresponding to a time when maximum liver uptake has occurred in the rat, 80% of the activity is still retained by the particles. Biodistribution studies in rats show that increasing the amount of HSA bound to IDE results in increasing liver uptake of this agent to more than 95% of injected dose. The intravenous LD50 of HSA-coated IDE in mice is greater than 3 gms iodine/kg body weight. Since the diagnostic dose for such an agent in hepatic CT scanning in humans is expected to be about 50 mg iodine/kg, the safety index (LD50/diagnostic dose) is greater than 60:1. The conclusion from these studies is that preincubation of iodipamide ethyl ester in human serum albumin results in improved efficacy and reduced toxicity such that the safety index is now better or comparable to that for currently used ionic water-soluble agents.