DRUG METABOLISM 8

LEARNING OBJECTIVES After completing this chapter, students will be able to: • Discuss the key concepts governing drug metabolism. • Explain the general mechanistic requirements for cytochrome P450 oxidation, as well as identify the factors that can alter the effects of these enzymes. • Predict the possible metabolic transformations that could occur for a given drug molecule. o For any given functional group within a drug molecule, identify the possible types of metabolic transformations it could undergo. o For each Phase I metabolic transformation, draw key intermediates and/or the final metabolic product. o For each Phase II metabolic transformation, draw and/or identify the acti- vated intermediate, identify the transferring enzyme, identify the functional groups that can be conjugated by this path, and/or identify any deconju- gating enzymes.

The primary purpose of drug metabolism is to enhance the removal of drug mole- cules from the body by altering or adding functional groups. Drug metabolism is also important for activating prodrugs, converting less active drugs to more active metabolites, inactivating drug action, deactivating toxic compounds, and in some cases producing toxic metabolites. Metabolic transformations can be divided into two main categories, Phase I metabolism and Phase II metabolism: • Phase I metabolic transformations include oxidation, reduction, and hydrolysis, with oxidation being the most prevalent of these three. In general, these transformations increase the water solubility of the drug molecule; however, this increase is not always sufficient enough to allow the drug to be readily excreted.

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• Phase II metabolic transformations all involve the addition of endogenous substances to the drug molecule. This process is known as conjugation. The most common Phase II conjugations involve the addition of glucuronic acid, sulfate, or the amino acids glycine or glutamine to functional groups that were either originally present in a drug molecule or added/unmasked by one or more Phase I processes. These conjugated products are highly water soluble, render the drug inactive in most cases, and are readily excreted. Additional Phase II processes involve the addition of glutathione, methyl groups, and acetyl groups to the drug molecule. Glutathione detoxifies highly reactive functional groups, while methylation and acetylation gener- ally terminate biological activity. With the exception of glutathione, there is an initial activation step resulting in the formation of a reactive coenzyme prior to the conjugate being transferred to the drug molecule. Additionally, deconjugating enzymes such as β-glucuronidase and sulfatase can reverse some of these Phase II processes. This chapter focuses on the common principles of drug metabolism, the mechanisms of Phase I and Phase II metabolic processes, and the functional groups susceptible to each type of transformation. The activation of prodrugs will also be discussed when applicable. Further discussions regarding the benefits of prodrugs can be found in Chapters 5 and 9. The primary purpose of this chapter is to illustrate the possible types of metabolic transformation that a drug molecule could undergo, thus enhancing a student’s ability to predict and understand metabolic pathways. As such, the examples presented in this chapter are not necessarily meant to portray the primary metabolic pathway for a given drug molecule. Instead, they are meant to illustrate the types of transformations that could occur based on the functional groups present in the drug molecule. For the sake of illustrating what is possible, a variety of drug molecules are used as examples. The actual metabolic route(s) for any given drug molecule are normally very specific and generally involve both major and minor pathways. Many of these are very predictable and others are not. By reviewing the various metabolic transformations and pathways that are outlined in this chapter, you should be better able to predict the metabolic transformations that can occur as well as understand how the actual metabolites are formed. For those who desire a more in-depth discussion of this topic, please consult the drug metabolism chapters found in Foye’s Principles of Medicinal Chemistry (7th edition), and Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry (12th edition).1,2