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All organisms are exposed to foreign chemical compounds (xenobiotics) in the air, water, and food. To ensure elimination of pharmacologically active xenobiotics and to terminate the action of many endogenous substances, evolution has provided metabolic pathways that alter such compounds’ activity and their susceptibility to excretion.

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Many cells in tissues that act as portals for entry of external molecules into the body (eg, pulmonary epithelium, intestinal epithelium) contain transporter molecules (MDR family [P-glycoproteins], MRP family, others) that expel unwanted molecules immediately after absorption. However, many foreign molecules evade these gatekeepers and are absorbed. Therefore, all higher organisms, especially terrestrial animals, require mechanisms for ridding themselves of toxic foreign molecules after they are absorbed, as well as mechanisms for excreting undesirable substances produced within the body. Biotransformation of drugs is one such process. It is an important mechanism by which the body terminates the action of many drugs. In some cases, it serves to activate prodrugs. Most drugs are relatively lipid-soluble as given, a characteristic needed for absorption across membranes. The same property would result in very slow removal from the body because the unchanged molecule would also be readily reabsorbed from the urine in the renal tubule. The body hastens excretion by transforming many drugs to less lipid-soluble, less readily reabsorbed forms.

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High-Yield Terms to Learn
Phase I reactions Reactions that convert the parent drug to a more polar (water-soluble) or more reactive product by unmasking or inserting a polar functional group such as —OH, —SH, or —NH2
Phase II reactions Reactions that increase water solubility by conjugation of the drug molecule with a polar moiety such as glucuronate, acetate, or sulfate
CYP isozymes Cytochrome P450 enzyme species (eg, CYP2D6 and CYP3A4) that are responsible for much of drug metabolism. Many isoforms of CYP have been recognized
Enzyme induction Stimulation of drug-metabolizing capacity; usually manifested in the liver by increased synthesis of smooth endoplasmic reticulum (which contains high concentrations of phase I enzymes)
P-glycoprotein, MDR-1 An ATP-dependent transport molecule found in many epithelial and cancer cells. The transporter expels drug molecules from the cytoplasm into the extracellular space. In epithelial cells, expulsion is via the external or luminal face


A. Phase I Reactions

Phase I reactions include oxidation (especially by the cytochrome P450 group of enzymes, also called mixed-function oxidases), reduction, deamination, and hydrolysis. Examples of phase I drug substrates are listed in Table 4–1. Phase I enzymes are found in high concentrations in the smooth endoplasmic reticulum of the liver. They are not highly selective in their substrates, so a relatively small number of P450 isoforms are able to metabolize thousands of drugs. Of the drugs metabolized by phase I cytochrome P450s, approximately 75% are metabolized by ...

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