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Exposure to xenobiotics immediately initiates a cascade to remove the foreign compound from the body’s circulation. The elimination of many drugs begins with a first pass effect, where orally administered drugs absorbed from the gastrointestinal tract into circulation pass through the liver before reaching targeted sites of action. Although the liver and kidneys are used to clear most compounds, other organs, including the skin and lungs, also assist with clearance. In most cases, the drug action terminates by enzyme-catalyzed conversion to inactive (or less active) compounds and/or elimination via the kidneys or other routes. Drug redistribution from the primary site may also terminate the action, although this occurs infrequently.


Biotransformation is a major mechanism for drug elimination. Most drugs undergo biotransformation to produce more polar metabolites than the administered drug. Excretion of compounds through renal and hepatic systems largely depends on lipophilicity or fat solubility. More lipophilic compounds tend to be reabsorbed back into circulation, either following renal glomerular filtration or through hepatic biliary excretion. Therefore, biotransformation of compounds into more polar (hydrophilic) structures is essential for complete removal of the drug. In addition, decreased drug lipophilicity limits a drug’s capacity to redistribute and accumulate in highly lipophilic areas, such as fat or brain tissue.

Many drugs undergo several sequential biotransformation reactions that are catalyzed by specific enzyme systems, primarily in the liver, which may also catalyze the biotransformation of endogenous compounds (ie, steroids). These reactions produce inactive drug metabolites; however, consequences of these reactions include secondary metabolites with increased or decreased potencies, metabolites with different pharmacological actions, toxic metabolites, and active metabolites from inactive prodrugs. The biotransformation of drugs is variable between individuals and is dependent on a multitude of factors, including age, diet, genetics, liver function, prior administration of the drug, and drug interactions.

Biotransformation reactions are classified into two types: phase I (nonsynthetic) and phase II (synthetic) reactions. Phase I reactions include oxidations, reductions, and hydrolysis reactions. These reactions typically introduce functional groups (ie, –OH, –SH, –NH2) that serve as active centers for subsequent phase II reactions. Enzymes catalyzing phase I reactions include cytochrome P450, aldehyde dehydrogenase, alcohol dehydrogenase, monoamine oxidase, deaminases, esterases, amidases, and epoxide hydrolase. Phase II reactions are conjugation reactions, involving an enzyme-catalyzed combination of endogenous compounds to functional groups produced from phase I reactions. These reactions utilize energy from “activated” forms of the endogenous compounds (ie, acetyl-CoA, UDP-glucuronate, glutathione). Enzymes catalyzing phase II reactions include glucuronyl transferase (conjugates glucuronyl group), sulfotransferase (conjugates sulfate group), transacylases (conjugates amino acids), glutathione S-transferase, acetylases, ethylases, and methylases.


Drug redistribution from primary target site to other storage sites, or reservoirs, is another mechanism by which the drug action terminates. Greater lipid solubility results in faster redistribution of drug to reservoirs. The underlying mechanism involves delivery of highly lipid-soluble drug to ...

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