NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

Cover of Molecular Imaging and Contrast Agent Database (MICAD)

Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

Show details

5-[3-Hydroxy-2-hydroxymethyl-propionamido)-N,N´-dimethyl-N,N´-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide

Iobitridol
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD, vog.hin.mln.ibcn@dacim

Created: ; Last Update: April 21, 2008.

Chemical name:5-[3-Hydroxy-2-hydroxymethyl-propionamido]-N-N´-dimethyl-N-N´-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamideimage 11110628 in the ncbi pubchem database
Abbreviated name:Iobitridol
Synonym:Xenetix®
Agent Category:Compound
Target:Non-targeted agent, blood pool, extracellular space
Target Category:Non-targeted filling of blood vessels and organs
Method of detection:X-ray, CT
Source of signal/contrast:Iodine (I)
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Non-primate non-rodent mammals
  • Checkbox Humans
Click on the above structure for additional information in PubChem.

Background

PubMed]

5-[3-Hydroxy-2-hydroxymethyl-propionamido)-N,N´-dimethyl-N,N´-bis-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (iobitridol) is a nonionic X-ray contrast agent used in various radiologic procedures to aid the radiographic visualization of selected tissues or organs.

X-Ray imaging (planar and tomographic) techniques depend on tissue density differences that provide the image contrast produced by X-ray attenuation between the area of interest and surrounding tissues (1, 2). 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 intravenous injectable forms have been developed for clinical applications (3, 4).

Water-soluble, intravenous X-ray contrast agents are generally organic iodine compounds that contain one or more tri-iodinated benzene rings (5, 6). When injected intravenously, they are largely distributed in the extracellular fluid space and excreted unchanged by the kidneys (7). 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 (3). 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 tolerability 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 (8). This was generally achieved by conversion of the carboxyl groups to hydroxyalkylamide groups (9).

As a low-osmolar nonionic monomer, iobitridol was developed in an effort to increase the safety and tolerance of X-ray contrast agents. The development of iobitridol was based on the belief that shielding of the hydrophobic areas of the 1,3,5-triiodobenzene ring from interaction with biological sites in vivo would decrease the chemotoxicity of this class of compounds (10-12). This compound is characterized by the introduction of a methyl group as second substituent in the tertiary amido group of the benzamide substituent chains to decrease the flexibility of the polar side-chains and to stabilize the hydrophilic sphere. However, Violon (13) compared iobitridol with four other nonionic monomers based on semi-empirical quantum mechanical calculations alone and concluded that the structured did not seem to stabilize the hydrophilic sphere to a greater extent than other studied molecules. Iobitridol is not commercially available in the United States but is available (250-350 mg iodine(I)/ml) in Europe for angiography, venography, and computed tomography (CT) examinations.

Synthesis

PubMed]

The processes involved in the production of X-ray contrast agents are well-established organic reactions (5). Hoey et al. (14) described the basic approach of synthesizing derivatives of isophthalamic acid as contrast agents. Schaefer et al. (15) reported the synthesis of iobitridol from 5-[2-isopropyl-1,3-dioxanne-5-carboxamido]-2,4,6-triiodoisophtaloyle dichloride. The compound was suspended in isopropanol and triethylamine to react with N-methyl-aminopropane-2,3-diol for 12 h at room temperature. The obtained product (68.5% yield) was then dissolved in 5 N hydrochloric acid and stirred for 12 h at room temperature. After filtering and evaporation, the final product was obtained with a yield of 90%.

In Vitro Studies: Testing in Cells and Tissues

PubMed]

Using in vitro experimental models, Idee et al. (16) tested iobitridol at an iodine dosage of 350 mg/ml. Studies of cardiac and pulmonary effects were carried out on hearts of New Zealand rabbits and the isolated guinea pig lung model. A transient decrease in myocardial contractility and a transient increase in pulmonary perfusion/ventilation pressure were observed. Similar effects were observed with another nonionic contrast agent, iohexol. The toxicity of iobitridol, as tested in vitro with human blood and cultured fibroblasts (red blood cell (RBC) morphology, RBC osmotic fragility and hemolysis, and fibroblast cell death) was similar to that of iohexol. Iobitridol showed slight histamine-releasing activity at the150 mg I/ml concentration. Donandieu et al. (17) reported no mutagenic or clastogenic activity for iobitridol, based on tests in bacteria and in vitro human lymphocyte metaphase analysis.

Dencausse et al. (18), using ultracentrifugation, determined that the in vitro human albumin binding of iobitridol was 2.1%. In vitro metabolism studies of iobitridol were performed with (rat, monkey, dog, rabbit, and human) hepatic microsomes. Depending on the species, one, two, or three metabolites were detected, and each metabolite constituted no more than 1.9% of injected dose (ID). There was only one metabolite in monkeys, dogs, and rabbits, but there were two metabolites in humans and three metabolites in rats.

Animal Studies

Rodents

PubMed]

Using 125I-labeled iobitridol (specific activity = 166.5 MBq (4.5 mCi)/mg) and whole-body quantitative autoradiography, Bourrinet et al. (19) studied the biodistribution of iobitridol in rats. The administered dose was 3.7 MBq (0.1 mCi) in a dose of 300 mg I/kg. At 1 h after administration, the tissue/plasma radioactivity ratios were 29.56 (unblocked thyroid), 11.80 (kidneys), 1.90 (skin), 1.28 (lungs), 1.18 (liver), and 0.62 (heart). Radioactivity in the brain was not detectable. By 24 h after administration, radioactivity was detected only in the thyroid. The major excretion organ was the kidneys, with 86% ID was eliminated in 24-48 h. Only 5% ID was excreted via the fecal route. Dencausse et al. (18) performed pharmacokinetic studies of 300 mg I/kg iobitridol in rats (n = 6) and determined the following parameters: elimination half-time ((t½β); 25 ± 1 min), mean residence time (36 ± 2 min), apparent distribution volume (236 ± 11 ml/kg), and clearance (2 ± 0 ml/min).

Idee et al. (16) reported the renal effects of iobitridol at the dose of 1 ml/min (350 mg I/ml) for 3 min in rats. Forty-eight hours after injection, Iobitridol appeared to induce fewer histologic lesions (vacuolization of tubular cells) than iohexol. Iobitridol also showed similar nociceptive effects of intra-arterial injections in rats. Tervahartiala et al. (20) studied the structural changes in the rat renal proximal tubular cells induced by iobitridol, iopamidol, and iohexol. Rats were deprived of water 24 h before injection of contrast agents at a dosage of 3 g I/kg. By 2 h after injection, iopamidol had induced moderate changes, but both iohexol and iobitridol had induced prominent lysosomal alterations. These changes induced by iobitridol had almost disappeared after 48 h.

Donandieu et al. (17) studied the toxicologic profile of iobitridol. The acute i.v. toxicity lethal dose (LD50) of iobitridol (350 mg I/ml) in mice was 15.9 g I/kg. In comparison, the LD50 for iohexol was also 15.9 I/kg. No acute oral toxicity was observed in mice up to 17.5 g I/kg. No deaths were observed after intracisternal injection. Subacute toxicity did not lead to any deaths in the rats at dosages up to 3.5 g I/kg/day for 28 days. No indication of embryo-fetal toxicity was observed in rats. No clastogenic activity was demonstrated through the micronucleus test in mice.

Other Non-Primate Mammals

PubMed]

Dencausse et al. (18) performed pharmacokinetic studies of 300 mg I/kg iobitridol in rabbits (n = 6) and determined the following parameters: elimination t½β (72 ± 6 min), mean residence time (90 ± 5 min), apparent distribution volume (267 ± 18 ml/kg), and clearance (7 ± 0 ml/min). The excretion was 92 ± 5% via urine and 0.73 ± 0.1% via feces in 24 h. In dogs (n = 6), these parameters were as follows: elimination t½β = 53 ± 3 min, mean residence time = 66 ± 4 min, apparent distribution volume = 252 ± 11 ml/kg, and clearance = 45 ± 3 ml/min. The excretion was 91 ± 2% via urine and 0.16 ± 0.03% via feces in 5 h.

Idee et al. (16) studied the in vivo bronchopulmonary effects, cardiopulmonary/renal effects, and neurologic effects of iobitridol in different animal models. No bronchospasms were observed in the guinea pig model. Cardiopulmonary and renal effects of iobitridol were similar to those of iohexol in dogs. No blood-brain barrier damage caused by iobitridol was observed in rabbits.

Donandieu et al. (17) reported no deaths and no systemic clinical toxicity signs after i.v. and perivenous injections of iobitridol in rabbits. Iobitridol appears to provoke only minimal reversible local reactions. No indication of teratogenicity was found in rabbits with iobitridol doses up to 3.5 g I/kg. No deaths were reported in dogs treated daily with iobitridol at doses up to 2.8 g I/kg.

Non-Human Primates

PubMed]

No publication is currently available.

Human Studies

PubMed]

Fournier et al. (21) evaluated the clinical safety and efficacy of iobitridol (350 mg I/ml) on 60 patients who underwent intravenous urography. The dose was 1 ml/kg up to a maximum total dose of 200 ml. The reported events were all very mild. There were 11 (18.3% of 60 patients) events of early, including transient warm sensation, and 2 events (3.3%) of nausea and vomiting. Image quality of iobitridol was judged to be good or excellent in 72-74% of the cases.

In a randomized double-blind phase III study, Hoogewoud and Woessmer (22) reported on the clinical safety of iobitridol (300 mg I/ml) compared with another monomeric nonionic contrast agent, iopromid, in 60 patients who had abdominal CT. They found that both iobitridol and iopromide provided similar image quality and side effects. Bach et al. (23) studied the effects of iobitridol on downstream capillary perfusion in a prospective, randomized, double-blind phase IV clinical trial. The study examined the cutaneous microcirculation in patients who underwent diagnostic cardiac catheter examination. The capillary erythrocyte velocity (VRBC) was measured before and up to 3 min after the injection of the contrast agent. The mean difference in VRBC between the baseline value and the maximum decrease after injection (Vdiff-max) of iobitridol (350 mg I/ml) was –0.07 mm/s in 10 patients. In comparison, the Vdiff-max values for iopromide (370 mg I/ml) and iodixanol (320 mg I/ml); a dimeric, nonionic contrast agent) were –0.23 and –0.22, respectively. The authors suggested that the microcirculatory disturbance induced by iobitridol was less severe than with other nonionic contrast agents.

Vogl et al. (24) reviewed the rate of adverse events associated with iobitridol in the general patient population and at-risk patients. The review included 210 radiologists who conducted various examinations in 52,057 patients. The adverse event rates were 0.96% and 1.39% for all patients and at-risk patients, respectively. The most frequent adverse events were sensation of heat (0.31%), nausea (0.24%), and urticaria (0.12%). The frequencies of all other events were less than 0.01%. The serious event rate was 0.044% in all patients and 0.057% in at-risk patients. These serious events included dyspnea (0.033%), hypotension (0.008%), and anaphylactic shock (0.006%). Petersein et al. (25) reported the results of a postmarketing surveillance study with iobitridol at various doses (1.5% of patients receiving 250 mg I/kg, 92.7% receiving 300 mg I/kg, and 5.8% receiving 350 mg I/kg) in 61,754 patients from 1996 to 2000. The adverse event rate was 2.3% of all of the examinations. The most frequent events were feeling of warmth (2.3%), nausea (1.3%), and urticaria (0.1%). Subjective assessment of image quality indicated that 99.0% of 60,021 examinations were diagnostic. Image quality assessment indicated that images were excellent or good in 90.5% and 90.6% of normal weight and overweight patients, respectively.

Various other studies [PubMed] have indicated that iobitridol is at least as safe and effective as other commercially available nonionic contrast agents.

Supplemental Information

[Disclaimers]

Iobitridol products.

References

1.
Swanson, D.P. and M.B. Alpern, Contrast media for computed tomography: Intravascular, intracavitary, xenon, reticuloendothelial, in Pharmaceuticals in medical imaging, D.P. Swanson, H. M. Chilton and J. H. Thrall, Editor. 1990, Macmillan Publishing Company: New York. p. 99-124.
2.
Hoey, G.B. and K.R. Smith, Chemistry of X-ray contras media, in Radiocontrast agents, M. Sovak, Editor. 1984, Springer-Verlag: New York. p. 23-125.
3.
Wallingford V.H. The development of organic iodine compounds as x-ray contrast media. J Am Pharm Assoc Am Pharm Assoc Baltim. 1953;42(12):721–8. [PubMed: 13108780]
4.
Sovak, M., R. Ranganathan, J.H. Lang, and E.C. Lasser, Concepts in design of improved intravascular contrast agents. European Society of cardiovascular Radiology, Uppsala, 1977(May): p. 25-27.
5.
Gries, H., Chemistry of X-ray contrast agents, in Textbook of contrast media, P. Dawson, D.O. Cosgrove, and R.G. Grainger, Editors. 1999, Isis Medical Media Ltd.: Oxford. p. 15-22.
6.
Almen T. Contrast agent design. Some aspects on the synthesis of water soluble contrast agents of low osmolality. J Theor Biol. 1969;24(2):216–26. [PubMed: 5822653]
7.
Dawson, P., Pharmacokinetics of water-soluble iodinated X-ray contrast agents, in Textbook of contrast media, P. Dawson, D.O. Cosgrove, and R.G. Grainger, Editors. 1999, Isis Medical Media Oxford. p. 61-74.
8.
Ralston W.H., Robbins M.S., Coveney J., Blair M. Acute and subacute toxicity studies of ioversol in experimental animals Invest Radiol 198924Suppl 1S2–9. [PubMed: 2592169]
9.
Almen T. Development of nonionic contrast media Invest Radiol 198520Suppl1S2–9. [PubMed: 2579043]
10.
Meyer D., Petta M., Fouchet M.H., Vadel M., Schaefer M., Dugast-Zrihen M., Guillemot M. Stabilization of the hydrophilic sphere of iobitridol, a new nonionic iodinated contrast agent. Acta Radiol Suppl. 1996;400:8–16. [PubMed: 8619359]
11.
Carrupt P.A., Testa B. Stabilization of the hydrophilic sphere of iobitridol. Br J Radiol. 2003;76(902):147. [PubMed: 12642287]
12.
Meyer D., Fouchet M.H., Petta M., Carrupt P.A., Gaillard P., Testa B. Stabilization of the hydrophilic sphere of iobitridol, an iodinated contrast agent, as revealed by experimental and computational investigations. Pharm Res. 1995;12(11):1583–91. [PubMed: 8592654]
13.
Violon D. Stabilization of the hydrophilic sphere of non-ionic monomers: are all protected in a similar way? Br J Radiol. 2001;74(888):1097–102. [PubMed: 11777766]
14.
Hoey G.B., Rands R.D., DeLaMater G., Chapman D.W., Wiegert P.E. Synthesis of derivatives of isophthalamic acid as X-ray contrast agents. 1963. [PubMed: 14174024]
15.
Schaefer M., D.-Z. D.-Z. M., Guillemot M., Doucet D., Meyer D. Iodinated non-ionic triiodobenzene compounds and contrast media containing them, U.S. Patent Number 5,043,1521991, United States Patient Office: U.S. p. 1-13.
16.
Idee J.M., Bault C., Beaufils H., Berthommier C., Cambar J., Corot C., Doucet D., Hartl C., Jaudon M.C., Jacquiaud C., Lakhdar B., Potier M., santus R., Torcherie S., Vaudon E., Bonnemain B. Pharmacologic profile of iobitridol, a nonionic iodinated contrast medium. Acta Radiol Suppl. 1996;400:35–48. [PubMed: 8619351]
17.
Donandieu A.M., Idee J.M., Doucet D., Legros A., Penati S., Nain-Dit-Ducret M., Marmion F., Bonnemain B. Toxicologic profile of iobitridol, a new nonionic low-osmolality contrast medium. Acta Radiol Suppl. 1996;400:17–24. [PubMed: 8619348]
18.
Dencausse A., Violas X., Feldman H., Havard P., Chambon C. Pharmacokinetic profile of iobitridol. Acta Radiol Suppl. 1996;400:25–34. [PubMed: 8619349]
19.
Bourrinet P., Dencausse A., Cochet P., Bromet-Petit M., Chambon C. Whole body quantitative autoradiographic study of the biodistribution of iobitridol in rats. Invest Radiol. 1994;29(12):1057–60. [PubMed: 7721547]
20.
Tervahartiala P., Kivisaari L., Kivisaari R., Vehmas T., Virtanen I. Structural changes in the renal proximal tubular cells induced by iodinated contrast media. Nephron. 1997;76(1):96–102. [PubMed: 9171307]
21.
Fournier P.J., Steinbrich W., Freitag P., Voegeli E. Evaluation of the clinical safety and efficacy of iobitridol (Xenetix) in intravenous urography. Eur J Radiol. 1996;23(3):185–9. [PubMed: 9003922]
22.
Hoogewoud H.M., Woessmer B. Iobitridol 300 compared to iopromide 300--a double-blind randomized phase-III study of clinical tolerance in total body CT. Acta Radiol Suppl. 1996;400:62–4. [PubMed: 8619354]
23.
Bach R., Gerk U., Mrowietz C., Jung F. Influence of a new monomeric nonionic radiographic contrast medium (iobitridol-350 versus NaCl) on cutaneous microcirculation: single-center, prospective, randomized, double-blind phase IV study in parallel group design. Microvasc Res. 2000;60(3):193–200. [PubMed: 11078635]
24.
Vogl T.J., Honold E., Wolf M., Mohajeri H., Hammerstingl R. Safety of iobitridol in the general population and at-risk patients. Eur Radiol. 2006;21:1–10. [PubMed: 16429272]
25.
Petersein J., Peters C.R., Wolf M., Hamm B. Results of the safety and efficacy of iobitridol in more than 61,000 patients. Eur Radiol. 2003;13(8):2006–11. [PubMed: 12942302]
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • PDF version of this page (814K)
  • MICAD Summary (CSV file)

Search MICAD

Limit my Search:


Related information

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...