Enzyme-responsive contrast agents

Most drugs used in anaesthesia are metabolised in the liver by phase I reactions, mediated by cytochrome P-450 enzymes. These are susceptible to destruction by cirrhosis, so that the biotransformation of drugs, such as opioids (except morphine), benzodiazepines, barbiturates, and inhalational agents, may be markedly altered in severe liver disease. These enzymes are found in the centrilobular areas, which are more prone to hypoxia. In contrast, the enzymes responsible for phase II reactions, found predominantly in the peripheral areas, often function normally even in advanced disease. The disposition of benzodiazepines that are eliminated primarily by glucuronidation, e.g. lorazepam and oxazepam, are unaffected by chronic liver disease. For drugs with low hepatic extraction, advanced hepatocytic dysfunction decreases phase I and II biotransformation with a reduced clearance and prolongation of the elimination half-life. This is often partially offset by an increased free fraction due to decreased protein binding. 

As important as calcium is probably iron [122]. Iron is the metal center of many essential proteins and enzymes, such as hemoglobin, an oxygen carrier, or peroxidase, that oxidizes hydrogen peroxide, or even the large family of cytochromes, which act as electron transfer proteins in many important biochemical processes [85]. New families of MRI contrast agents have been designed such that their relaxivity is iron concentration dependent [128-130]. The two latest are based on Gd(III) chelates (Fig. 20) but differ by the mechanism responsible for their iron sensitivity and will be described further. 

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