CLINICAL PHARMACOLOGY
Following intravascular injection, MD-76R is rapidly transported through the bloodstream to the kidneys and is excreted unchanged in the urine by glomerular filtration. The pharmacokinetics of intravascularly administered radiopaque contrast media are usually best described by a two compartment model with a rapid alpha phase for drug distribution and a slower beta phase for drug elimination. In patients with normal renal function, the alpha and beta half-lives of MD-76R were approximately 10 and 100 minutes, respectively.
Renal accumulation is sufficiently rapid that the period of maximal opacification of the renal passages may begin as early as 5 minutes after injection. In infants and small children excretion takes place somewhat more promptly than in adults, so that maximal opacification occurs more rapidly and is less sustained. The normal kidney eliminates the contrast medium almost immediately. In nephropathic conditions, particularly when excretory capacity has been altered, the rate of excretion varies unpredictably, and opacification may be delayed for 30 minutes or more after injection; with severe impairment opacification may not occur. Generally, however, the medium is concentrated in sufficient amounts and promptly enough to permit a thorough evaluation of the anatomy and physiology of the urinary tract. Intravascular injection also opacifies those vessels in the path of flow of the medium, permitting visualization until the circulating blood dilutes the concentration of the medium. Thus selective angiography may be performed following injection directly into veins or arteries.
Injectable iodinated contrast agents are excreted either through the kidneys or through the liver. These two excretory pathways are not mutually exclusive, but the main route of excretion seems to be related to the affinity of the contrast medium for serum albumin. Diatrizoate salts are poorly bound to serum albumin, and are excreted mainly through the kidneys.
The liver and small intestine provide the major alternate route of excretion. In patients with severe renal impairment, the excretion of this contrast medium through the gallbladder and into the small intestine sharply increases.
Diatrizoate salts cross the placental barrier in humans and are excreted in human milk.
CT Scanning of the Head
When used for contrast enhancement in computed tomographic brain scanning, the degree of enhancement is directly related to the amount of iodine administered. Rapid injection of the entire dose yields peak blood iodine concentrations immediately following the injection, which fall rapidly over the next five to ten minutes. This can be accounted for by the dilution in the vascular and extracellular fluid compartments which causes an initial sharp fall in plasma concentration. Equilibration with the extracellular compartments is reached by about ten minutes; thereafter the fall becomes exponential. Maximum contrast enhancement frequently occurs after peak blood iodine levels are reached. The delay in maximum contrast enhancement can range from five to forty minutes, depending on the peak iodine levels achieved and the cell type of the lesion. This lag suggests that the contrast enhancement of the image is at least in part dependent on the accumulation of iodine within the lesion and outside the blood pool.
In brain scanning, the contrast medium (MD-76R) does not accumulate in normal brain tissue due to the presence of the “blood brain barrier”. The increase in x-ray absorption in the normal brain is due to the presence of the contrast agent within the blood pool. A break in the blood brain barrier, such as occurs in malignant tumors of the brain, allows accumulation of contrast medium within the interstitial tumor tissue; adjacent normal brain tissue does not contain the contrast medium.
The image enhancement of non-tumoral lesions, such as arteriovenous malformations and aneurysms, is dependent on the iodine content of the circulating blood pool.
CT Scanning of the Body1
In non-neural tissues (during CT of the body), MD-76R diffuses rapidly from the vascular to the extra-vascular space. Increase in x-ray absorption is related to blood flow, concentration of the contrast medium and extraction of the contrast medium by interstitial tissue since no barrier exists; contrast enhancement is thus due to the relative differences in extra-vascular diffusion between normal and abnormal tissue, a situation quite different than that in the brain.
The pharmacokinetics of MD-76R in normal and abnormal tissues has been shown to be variable.
Enhancement of CT with MD-76R may be of benefit in establishing diagnoses of certain lesions in some sites with greater assurance than is possible with unenhanced CT and in supplying additional features of the lesions. In other cases, the contrast medium may allow visualization of lesions not seen with CT alone or may help to define suspicious lesions seen with unenhanced CT.
Contrast enhancement appears to be greatest within the 30-90 seconds after bolus administration of the contrast agent, and after intra-arterial rather than intravenous administration. Therefore, the use of a continuous scanning technique (a series of 2-3 second scans beginning at the injection—dynamic CT scanning) may improve enhancement and diagnostic assessment of tumors and other lesions, occasionally revealing more extensive disease. A cyst, or similar non-vascularized lesion may be distinguished from vascularized solid lesions by comparing enhanced and unenhanced scans; the non-vascularized lesions show no change in CT number, the vascularized lesions would show an increase. The latter might be benign, malignant or normal, but it is unlikely that it would be a cyst, hematoma, or other non-vascularized lesion.
Because unenhanced scanning may provide adequate information in the individual patient, the decision to employ contrast enhancement, which is associated with additional risk and increased radiation exposure, should be based upon a careful evaluation of clinical, other radiological, and unenhanced CT findings.
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