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KEY POINTS

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  • Biotransformation is the metabolic conversion of endogenous and xenobiotic chemicals to more water-soluble compounds.

  • Xenobiotic biotransformation is accomplished by a limited number of enzymes with broad substrate specificities.

  • Phase I reactions involve hydrolysis, reduction, and oxidation. These reactions expose or introduce a functional group (—OH, —NH2, —SH, or —COOH), and usually result in only a small increase in hydrophilicity.

  • Phase II biotransformation reactions include glucuronidation, sulfonation (more commonly called sulfation), acetylation, methylation, and conjugation with glutathione (mercapturic acid synthesis), which usually result in increased hydrophilicity and elimination.

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INTRODUCTION

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The enzymes that catalyze xenobiotic biotransformation are often called drug-metabolizing enzymes. The acronym ADME stands for absorption, distribution, metabolism, and elimination. This acronym is widely used in the pharmaceutical industry to describe the four main processes governing drug disposition. The acronym is sometimes extended to include drug transport (AMDET) or drug toxicity (ADME-Tox). This chapter describes some fundamental principles of xenobiotic biotransformation, and describes the major enzyme systems involved in the biotransformation (or metabolism) of drugs and other xenobiotics.

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GENERAL PRINCIPLES

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The following points, which might be considered principles or rules, apply in the majority of cases:

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Point 1 Xenobiotic biotransformation or drug metabolism is the process of converting lipophilic (fat-soluble) chemicals, which are readily absorbed from the gastrointestinal tract and other sites, into hydrophilic (water-soluble) chemicals, which are readily excreted in urine or bile. There are exceptions even to this most basic rule. For example, acetylation and methylation are biotransformation reactions that can actually decrease the water solubility of certain xenobiotics.

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Point 2 The biotransformation of xenobiotics is catalyzed by various enzyme systems that can be divided into four categories based on the reaction they catalyze: (1) hydrolysis (e.g., carboxylesterase); (2) reduction (e.g., carbonyl reductase); (3) oxidation (e.g., cytochrome P450 [CYP]); and (4) conjugation (e.g., UDP-glucuronosyltransferase [UGT]). The mammalian enzymes involved in the hydrolysis, reduction, oxidation, and conjugation of xenobiotics are listed in Table 6–1, together with their principal subcellular location.

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Table Graphic Jump Location
TABLE 6–1

General pathways of xenobiotic biotransformation and their major subcellular location.

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