Lorazepam, biotransformation

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. 

Table 1-2 includes a list of major CYPs that are responsible for the phase I metabolism of commonly used psychotropics as well as selected substances that are psychoactive and are commonly used by psychiatric patients. With very few exceptions (e.g., lithium does not require biotransformation lorazepam and oxazepam are directly conjugated without first going through oxidation), the pharmacokinetics of practically all psychotropics are dependent on one or more of the CYPs, whose activity significantly influences the tissue concentrations, dose requirement, and side-effect profiles of their substrates. 

Figure 5.6. Biotransformation pathways of delorazepam, lormetazepam, and lorazepam.

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