Small Molecule Drug Metabolism

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II. Where does metabolism occur in the body?  

 

The liver is the primary site for metabolism.  Liver contains the necessary enzymes for metabolism of drugs and other xenobiotics.  These enzymes induce two metabolism pathways: Phase I (functionalization reactions) and Phase II (biosynthetic reactions) metabolism.  Some typical examples of Phase I metabolism include oxidation and hydrolysis.  The enzymes involved in Phase I reactions are primarily located in the endoplasmic reticulum of the liver cell, they are called microsomal enzymes.  Phase II metabolism involves the introduction of a hydrophilic endogenous species, such as glucuronic acid or sulfate, to the drug molecule.  Enzymes involved in phase II reactions are mainly located in the cytosol, except glucuronidation enzyme, which is also a microsomal enzyme.

Drugs are usually lipophilic substances (Oil-like) so they can pass plasma membranes and reach the site of action.  Drug metabolism is basically a process that introduces hydrophilic functionailities onto the drug molecule to facilitate excretion.  When the drug molecule is oxidized, hydrolyzed, or covalently attached to a hydrophilic species, the whole molecule becomes more hydrophilic, and is excreted more easily.  Drugs often undergo both Phase I and II reactions before excretion.  The Phase I reaction introduces a functional group such as a hydroxyl group onto the molecule, or exposes a preexisting functional group, and Phase II reaction connects this functional group to the endogenous species such as a glucuronic acid.  The modified drug molecule may then be hydrophilic enough to be excreted.

Although liver is the primary site for metabolism, virtually all tissue cells have some metabolic activities.  Other organs having significant metabolic activities include the gastrointestinal tract, kidneys, and lungs.  When a drug is administrated orally, it undergoes metabolism in the GI track and the liver before reaching systemic circulation.  This process is called first-pass metabolism.  First-pass metabolism limits the oral bioavailability of drugs, sometimes significantly.  

 

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