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drugs may undergo first-pass metabolism, so that a proportion of the drug is inactivated before it reaches the target tissue.

The microsomal enzymes responsible for catalyzing oxidative and reductive reactions are the cytochrome P450 enzyme family. These are heme-containing membrane proteins that are found in the smooth endoplasmic reticulum of the cells of many tissues, but especially in the liver. Twelve gene families of the cytochrome P450 enzyme have been identified in humans, and the three families, CYP1, CYP2, and CYP3 account for most drug biotransformations. Hydrolytic reactions are carried out by the enzyme epoxide hydrolase and several amidases, esterases, proteases, and peptidases. Conjugation reactions are carried out by uridine diphosphate glucuronosyltransferases, sulfotransferases, and N-acetyltransferases.

Several factors may influence the processes of biotransformation. Certain drugs or toxins may induce synthesis of cytochrome P450. For drugs that are transformed into toxic metabolites, this may amount to significant hepatic or renal toxicity over time. A common example of this is with chronic alcoholism resulting in liver damage. Drugs may also inhibit cytochrome P450 enzymes, resulting in slower metabolism and prolonged drug concentrations. Unintentional interactions between diverse types of drugs may occur through competition for enzymes. For example, several studies have examined the inhibition of cytochrome P450 3A4 (CYP3A4) by grapefruit juice. Biotransformation may be reduced in cases of liver disease. It is also reduced in fetal and neonatal stages of development, and in many elderly. Genetic differences normally exist between individuals in drug metabolism capacity, which result from polymorphisms in the cytochrome P450 family. Excretion

Excretion is the process of eliminating drugs from the body. They may be excreted as metabolites or as unchanged drug. As mentioned above, compounds that are polar and water soluble are more readily eliminated. The major routes of excretion are renal, biliary/fecal, lactational, and pulmonary.

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