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Commentary |
1 Department of Radiology, University of California Davis Medical Center, 4860 Y St., Ste. 3100, Sacramento, CA 95817.
Received December 13, 2007; accepted after revision December 14, 2007.
Address correspondence to R. W. Katzberg
(richard.katzberg{at}ucdavis.edu).
Keywords: contrast media • excretory pathways • protein binding • toxicity
In 1962, a monumental article by Elliott Lasser et al. [1] was published in the American Journal of Radiology Radium Therapy Nuclear Medicine, presenting 23 pages, with 64 references, 18 figures, and five tables that included new data from eight research protocols. This publication was comprehensive and provided a wide-ranging synthesis of both laboratory and clinical work. The significance of protein binding by contrast media as an important factor in toxicity and excretory pathways was clearly elucidated for the first time. The significance of this publication was subsequently highlighted and referred to as the "Principle of Lasser" by the well-known pioneer and father of nonionic low-osmolar contrast media, Torsten Almén [2].
The presence of an unsubstituted hydrogen atom on the tri-iodinated benzene ring at both the 3 and 5 positions gives a higher degree of binding to proteins than when that hydrogen has been substituted (Fig. 1A, 1B). Lasser et al. [1] hypothesized that the increase in protein binding is not only a factor that incites anaphylactoid reactions but is also a physical–chemical phenomenon that governs excretory pathways and could serve as a guide for development of less-toxic agents and more organ-specific characteristics. Indeed, the evolution from acetrizoate (Urokon, Mallinckrodt Chemical Works [now Mallinckrodt Imaging]) to meglumine diatrizoate (Hypaque, Sanofi-Aventis) has led to higher biologic tolerance, as indicated by a median lethal dose (LD50) of 5 g of iodine per kilogram with acetrizoate versus 5–10 g with the diatrizoates. The higher clinical tolerability of diatrizoate resulted in its extensive use.
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Lasser et al. [1] then correlated characteristics of contrast media with alteration in blood and blood vessels. They observed that those agents with the higher albumin binding capacity produced a greater degree of RBC morphologic changes (crenation) than those agents that had poor protein binding. Evidence from their investigation and from the literature suggested that local and systemic toxicity from contrast materials is mediated via derangements of the blood elements and blood vessels. It was hypothesized that this is related to the proven presence of contrast-binding albumin sites in or on these structures.
Next, Lasser et al. [1] turned their attention to the relationship of contrast material protein binding and pathways of contrast material excretion. They observed that the more highly protein-bound contrast media appear to be preferentially excreted in the bile and the less highly bound media in the urine. This allows characterization of the types of contrast media best suited for hepatic versus renal excretion and imaging. All of the available chole cystographic contrast media in use at that time had the chemical configuration that confers good albumin binding. In contrast, all of the urographic contrast media were relatively poor albumin binders.
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Elliott Lasser has continued in the field of contrast media development, fathering an international contrast medium society and continuing his research in contrast media toxicity and development. His leadership is ongoing and inspirational. He attended and presented at the most recent Contrast Media Research meeting in Banff, Canada, in October 2007 (Fig. 2).
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