Iodixanol

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Abstract
Iodixanol is an iso-osmolal nonionic dimeric hydrophilic contrast agent. It has similar diagnostic efficacy to that of other iodinated contrast media. Because of its physical properties, iodixanol would be expected to produce a lower incidence of adverse events than other nondimeric contrast media. Indeed, pharmacodynamic studies indicate that iodixanol has fewer cardiovascular effects, causes less renal damage and is associated with similar or smaller changes to the blood-brain barrier and neurological function when compared with nondimeric nonionic contrast media. In clinical trials, iodixanol had a similar tolerability profile to other nonionic contrast media but induced fewer adverse events than ioxaglate. Iodixanol appears to have an advantage over other contrast media in that it generally causes less frequent and less intense discomfort on injection. However, in common with other newer, and usually nonionic, contrast media, iodixanol is expensive. Studies investigating other nonionic contrast media (but not iodixanol) have shown that it is not cost-effective in all patients to replace older, usually ionic, contrast media with the more costly newer alternatives. Nonetheless, in selected patients who are considered at increased risk of contrast medium-associated adverse events, nonionic agents should be used. Iodixanol, with its lower intensity (and possibly frequency) of discomfort, may be a preferred option in these patients. In addition to chemotoxicity, adverse events associated with contrast media are related to increases in osmolality and ionicity. Iodixanol is a dimeric nonionic contrast medium with lower osmolality and a higher iodine ratio than other nondimeric contrast media. Iodixanol has 9 hydroxyl groups and no carboxyl groups; presence of these groups is associated with reduced and increased toxicity, respectively. Iodixanol produced similar angiographic attenuation, indicating similar diagnostic efficacy, to ioxaglate and iohexol in animals or an experimental circulation model. Contrast media have been associated with several adverse events affecting the cardiovascular system. However, injection of iodixanol into the coronary arteries of dogs with or without left ventricular failure does not cause depression of myocardial function. Transient alteration in cardiac parameters and ventricular tachycardia or fibrillation occur at a lower frequency and/or intensity than similar effects produced by iohexol, iotrolan (another hexaiodinated iso-osmolar contrast medium), ioxaglate or iopamidol. Iodixanol and iotrolan produce similar haemo-dynamic changes in pigs. Although intra-arterial injection of iodixanol 320 mgI/ml causes undesirable peripheral vasodilation in patients undergoing femoral arteriography, studies conducted in dogs or rabbits showed that iodixanol induced significantly smaller changes in blood flow than the same iodine concentrations of iohexol, iopentol, iopromide or metrizoate. Iodixanol, iopamidol, iopentol and iohexol all reduced erythrocyte aggregation in vitro by a similar extensive amount, but diatrizoate induced significantly more erythrocyte rigidification. The nonionic contrast media also induced morphological changes in erythrocytes with stomatocyte and echinocyte deformation occurring. However, iodixanol was the only agent that did not produce desiccocytes. Leucocyte phagocytosis, adherence and degranulation were also inhibited by contrast media, with iodixanol having the least effect. In healthy volunteers, iodixanol acts as an osmodiuretic and produces a dose-dependent increase in urine volume. Iodixanol 1.2 gI/kg increased osmolar clearance and urinary sodium, N-acetyl-/gb-glucosamidase and β2-microglobulin excretion to a smaller extent, but induced a more prolonged increase in urinary alkaline phosphatase excretion and greater delayed corticomedullary attenuation than iopamidol or iopentol (at the same iodine dose). However, iodixanol caused less formation of large cytoplasmic vacuoles than iohexol, iopentol, iopromide, ioxaglate or metrizoate in renal epithelial cell lines from proximal and distal tubules. Glomerular filtration rate is not affected by nonionic contrast media. In rabbits, experimental carotid angiography with iohexol, iodixanol, ioversoi or iotrolan all had similar disruptive effects on the blood-brain barrier that tended to correlate with hydrophilicity of the contrast media rather than with osmolality. Subarachnoid injection of iodixanol induced a lower excitatory response in rabbits than iotrolan, but more excitation than iohexol. In general, few adverse neural effects of iodixanol were noted in studies conducted in mice or dogs. Iodixanol has a pharmacokinetic profile similar to that of many other nonionic contrast media. After intravenous injection of iodixanol in healthy volunteers, peak serum iodixanol concentrations are rapidly achieved. Serum concentrations then decrease biexponentially: little drug is detected 24 hours after administration. Iodixanol distributes only in the extracellular fluid. Distribution half-life (t½α), elimination half-life (t½β) and apparent volume of distribution are not dose-dependent, with mean values of 0.43 and 2.18 hours and 0.275 L/kg, respectively, for iodixanol 0.3 to 1.2 gl/kg. Iodixanol is not metabolised and is predominantly excreted in the urine by glomerular filtration. At least 97% of an injected dose is excreted unchanged in the urine within 24 hours and 1.2% is excreted unchanged in the faeces within 72 hours. The pharmacokinetic profile of iodixanol in elderly patients appears to be affected more by renal function than age. Iodixanol has similar distribution pharmacokinetics in patients with stable but severely impaired renal function (serum creatinine level >400 μmol/L or creatinine clearance vs 96.3%; p < 0.02) in patients undergoing femoral arteriography. Other haemodynamic changes were generally not significantly different with iodixanol and ioxaglate or iohexol in patients undergoing cardioangiography. However, in 2 studies, ioxaglate induced a greater increase in mean heart rate than iodixanol. Large reductions (>20mm Hg) in diastolic blood pressure occurred in more iodixanol than iohexol recipients, but large increases (≥20mm Hg) occurred in fewer iodixanol than ioxaglate recipients. Renal function changes were generally considered to be clinically unimportant and were transient in patients undergoing aortofemoral angiography with iodixanol, iopromide, iohexol or ioxaglate. Indeed, iodixanol or iohexol produced only a small transient reduction in glomerular filtration rate in 16 well-hydrated patients with chronic renal failure undergoing angiography. Iodixanol may have a greater effect on glomerular function than some other contrast media, but less effect on tubular function. Iodixanol is formulated in 3 strengths depending on iodine content (150, 270 and 320 mgI/ml) and is mixed with electrolytes (sodium and calcium chloride) to produce an isotonic solution and to reduce the likelihood of unwanted arrhythmogenic activity. Iodixanol is administered intravenously or intra-arterially at a dosage that depends on the type of examination, technique used and patient characteristics. The iodine concentration and volume given is approximately the same as is used with other contrast media and, as with all these agents, adequate hydration should be maintained before and after administration. Studies have been conducted in children, but results are not yet available. Contrast media are used to increase the difference in attenuation of radiation between various tissues or organs to allow better visualisation of structures within the body. The ideal contrast medium should be highly water soluble and biologically inert and have heat and chemical stability, low viscosity, osmolality less than or equal to that of plasma, selective excretion, good tolerability and reasonable cost.[1] This review discusses iodixanol, an isotonic and iso-osmotic contrast medium with favourable pharmacological properties (section 1) which appears to have tolerability advantages over most other contrast agents (sections 2 and 5). Iodixanol has also been investigated for use as a nonionic iso-osmotic density gradient centrifugation medium;[2] however, this application is not discussed here.

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