Timothy S. Tracy
Both metabolism and excretion can be viewed as processes responsible for elimination of drug (parent and metabolite) from the body. Drug metabolism changes the chemical structure of a drug to produce a drug metabolite, which is frequently but not universally less pharmacologically active. Metabolism also renders the drug compound more water soluble and therefore more easily excreted.
Drug metabolism reactions are carried out by enzyme systems that evolved over time to protect the body from exogenous chemicals. The enzyme systems for this purpose for the most part can be grouped into two categories: phase I oxidative or reductive enzymes and phase II conjugative enzymes. Enzymes within these categories exhibit some limited specificity in relation to the substrates acted upon; a given enzyme may interact with only a limited number of drugs. Some nonspecific hydrolytic enzymes, such as esterases and ami-dases, have not received much research attention. The focus of this discussion therefore is on phase I and phase II reactions and the enzymes that carry out these processes.
OXIDATIVE AND REDUCTIVE ENZYMES: PHASE I REACTIONS
Phase I enzymes act by causing the drug molecule to undergo oxidation or more rarely, reduction. Examples of oxidation reactions carried out by phase I enzymes are listed in Table 4.1 and encompass a broad range of drugs with varying chemical structures. However, as discussed later, there is still a great deal of substrate specificity within a given enzyme family.
The cytochrome P450 (CYP450) enzyme superfamily is the primary phase I enzyme system involved in the ox-idative metabolism of drugs and other chemicals. These enzymes also are responsible for all or part of the metabolism and synthesis of a number of endogenous compounds, such as steroid hormones and prostaglandins.
Though it was originally described as the CYP450 enzyme, it is now apparent that it is a group of related enzymes, each with its own substrate specificity. To date, 12 unique isoforms (e.g., CYP3A4, CYP2D6) have been identified as playing a role in human drug metabolism, and others may be discovered. These isoforms, along with examples of compounds for which each isoform plays a substantial role in their metabolism, are listed in Table 4.2. More than one CYP isoform may be involved in the metabolism of a particular drug. For example, the calcium channel blocking drug verapamil is primarily metabolized by CYP3A4, but CYPs 2C9, 2C8 and 2D6 participate to some degree, particularly in the secondary metabolism of the verapamil metabolites. Thus, the degree to which a drug interaction involving competition for a CYP isoform may occur will depend on the extent of metabolism of each compound that can be attributed to that isoform. The more isoforms involved in the metabolism of a drug, the less likely is a clinically significant drug interaction.
CYP3A4 is thought to be the most predominant CYP isoform involved in human drug metabolism, both in terms of the amount of enzyme in the liver and the variety of drugs that are substrates for this enzyme isoform.
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