N-(2,3-dihydroxypropyl)-N´-(2-hydroxyethyl)-5-[N-(2,3-dihydroxypropyl)acetamido]-2,4,6-triiodoisophthalamide (ioxilan) is a nonionic X-ray contrast agent approved by the United States Food and Drug Administration for X-ray imaging contrast enhancement (1, 2). Ioxilan can be administered intravenously for excretory urography and contrast-enhanced computed tomography (CT) imaging of the head and body (3). Ioxilan can also be given intraarterially for cerebral arteriograpy, coronary arteriography and left ventriculography, visceral angiography, aortography, and peripheral arteriography.
Techniques for X-ray imaging (planar and tomographic) depend on tissue density differences that provide the image contrast produced by X-ray attenuation between the area of interest and its surrounding tissues (4, 5). Contrast enhancement (opacification) with use of contrast agents increases the degree of contrast and improves the differentiation of pathologic processes from normal tissues. Because iodine, an element of high atomic density, causes high attenuation of X-rays within the diagnostic energy spectrum, water-soluble and reasonably safe iodinated contrast agents in intravenously injectable forms have been developed for clinical applications (6, 7).
Water-soluble, intravenous X-ray contrast agents are generally organic iodine compounds that contain one or more tri-iodinated benzene rings (8, 9). When injected intravenously, they are largely distributed in the extracellular fluid space and excreted unchanged by the kidneys (10). Contrast enhancement of a region of interest depends on the route of administration, delivery of the agent to the area by blood flow, and the final iodine concentration in the region. There are two basic types of these compounds: ionic and nonionic agents. The first monomeric ionic compound, in the form of 2,4,6-triiodobenzene acetrizoic acid, was synthesized by Wallingford (6). Most ionic contrast agents are derived from the basic structures of 3,5-diamino-2,4,6-triiodobenzoic acid, 5-amino-2,4,5-triiodoisophthalic acid, or 2,4,6-triiodobenzene-1,3,5-tricarbonic acid. In addition to monoacidic ionic dimers, nonionic compounds have also been developed to improve the tolerance of these agents in patients. The basic strategy of developing nonionic agents is to eliminate the electrical charges in the structure, which will lead to a reduction in osmolality of the compound. Because osmolality is related to the number of particles in solution, the challenge is to reduce the number of particles but maintain the iodine concentration (11). This is generally achieved by conversion of the carboxyl groups to hydroxyalkylamide groups (12).
As a low-osmolar nonionic monomer, ioxilan was developed in an effort to increase the safety and tolerance of X-ray contrast agents. The development of ioxilan was based on the belief that the introduction of a double methylene as a hydrophobic region and masking it with a hydrophilic hydroxyl group could lower the osmolality without adversely affecting the biological tolerance (13). Ioxilan is available commercially in preparations of 300 mg I/ml (632 mg ioxilan) and 350 mg I/ml (727 mg ioxilan). Their measured osmolality values (mOsm/kg water) at 37ºC are 585 and 695, respectively. The viscosity values (cP) at 37ºC are 5.1 and 8.1, respectively.