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Substances foreign to the body, or xenobiotics, are metabolized by the same enzymatic pathways and transport systems that are used for normal metabolism of dietary constituents. Drugs are considered xenobiotics and most are extensively metabolized in humans. The capacity to metabolize xenobiotics has made development of drugs very time consuming and costly due in large part to:


  • Interindividual variations in the capacity of humans to metabolize drugs

  • Drug-drug interactions

  • Metabolic activation of chemicals to toxic and carcinogenic derivatives

  • Species differences in expression of enzymes that metabolize drugs, thereby limiting the use of animal models to predict effects in humans


Most xenobiotics are subjected to 1 or multiple enzymatic pathways that constitute phase 1 oxidation and phase 2 conjugation. Metabolism serves to convert these hydrophobic chemicals into more hydrophilic derivatives that can easily be eliminated from the body through the urine or the bile.


Many drugs are hydrophobic, a property that allows entry through the lipid bilayers into cells where the agents can interact with their target receptors or proteins. This property of hydrophobicity renders drugs difficult to eliminate, because in the absence of metabolism, they accumulate in fat and cellular phospholipid bilayers in cells. The xenobiotic-metabolizing enzymes convert drugs and other xenobiotics into derivatives that are more hydrophilic and thus easily eliminated through excretion into the aqueous compartments of the tissues.

Drug metabolism that leads to elimination also plays a major role in diminishing the biological activity of a drug. For example, (S)-phenytoin, an anticonvulsant used in the treatment of epilepsy, is virtually insoluble in water. Metabolism by the phase 1 cytochromes P450 (CYPs) followed by phase 2 uridine diphosphate-glucuronosyltransferases (UGTs) produces a metabolite that is highly water soluble and readily eliminated from the body (Figure 6–1). Metabolism also terminates the biological activity of the drug.

Paradoxically, these drug metabolizing enzymes can also convert certain chemicals to highly reactive, toxic, and carcinogenic metabolites or carcinogens. Depending on the structure of the chemical substrate, xenobiotic-metabolizing enzymes can produce electrophilic metabolites that react with nucleophilic cellular macromolecules such as DNA, RNA, and protein. Reaction of these electrophiles with DNA can sometimes result in cancer through the mutation of genes, such as oncogenes or tumor suppressor genes. This potential for carcinogenic activity makes testing the safety of drug candidates of vital importance, particularly for drugs that will be used chronically.

Figure 6–1

Metabolism of phenytoin by phase 1 cytochrome P450 (CYP) and phase 2 uridine diphosphate-glucuronosyltransferase (UGT). CYP facilitates 4-hydroxylation of phenytoin. The hydroxy group serves as a substrate for UGT that conjugates a molecule of glucuronic acid (in green) using UDP-glucuronic acid (UDP-GA) as a cofactor. This converts a very hydrophobic molecule to a larger hydrophilic derivative that is eliminated via the bile.

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