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Metabolism

These CYP enzymes are present in every cell and are responsible for metabolizing or detoxifying consumed foreign (i.e., xeno) biological substances (e.g., toxins, carcinogens, mutagens and drugs). The enzymes primarily involved in drug metabolism are located in the liver. About 30 of these enzymes — especially the CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 isozymes — are primarily located in endoplasmic reticulum of hepatocytes in the liver and in the small intestine, with smaller quantities in the kidneys, lungs and brain.These enzymes play a major role in the metabolism of most drugs commonly used today. The CYP2E1 isozyme is more involved with inactivation of toxins than with drug metabolism.

The specific CYP isozyme responsible for the metabolism of many drugs, especially those marketed before 1980, is generally unknown. However, most if not all newer drugs have been identified in clinical trials as substrates, inducers, and/or inhibitors of certain CYP enzymes. A drug that inhibits a specific CYP isozyme may decrease the metabolism of the drug and increase serum concentrations of drugs that are substrates for that isoenzyme. Conversely, a drug that induces a specific CYP isozyme may increase the metabolism of the drug and decrease serum concentrations of drugs that are substrates for that isozyme. In general, the extent of CYP isozyme induction or inhibition increases significantly as the dose of the drug increases and/or duration of treatment increases.Pharmaceuticals in the same chemical class may vary quantitatively on their affinity for specific CYP enzymes. Some drugs are substrates for multiple CYP isozymes. Some drugs are racemic mixtures of stereoisomers and may be substrates for different isozymes and have varying affinity for the isozymes. The CYP family enzyme, its subfamily, and the individual enzyme are involved with metabolism of a drug, but the drug will be primarily metabolized by one specific enzyme.

Although pharmaceutical manufacturers may include in a drug monograph that drug “A” is a substrate for a CYP isozyme, the extent of its metabolism may not be known. In some instances, the degree to which a drug is metabolized by an isozyme may only be minimal, about 10%, or it may be extensively metabolized. Metabolism of the remaining drug will be modulated by other biochemical processes. The CYP enzymes are involved in converting pharmacologically active lipid-soluble compounds into usually inactive polar compounds, primarily through Phase I, oxidation, demethylation and hydroxlylation reactions.

Overall drug metabolism in the liver mediated by CYP enzymes is generally depressed during the first month post-transplantation, but recovers during the next few months. Interestingly, CYP2D6 appears to be unaffected by transplantation, while the activity of CYP2E1 enzyme is enhanced during the first month in liver transplant patients. Unless there is major liver damage or abuse, the CYP system’s activity generally remains at least adequate throughout life. Although liver function tests (e.g., AST, ALT) may be modestly elevated, there does not seem to a corresponding decrease in CYP enzyme metabolism.

The kidneys are usually known for their ability to excrete water, electrolytes, drugs and other chemicals. However, they are very active in the biotransformation of a variety of drugs. The CYP enzyme system in the kidneys has been identified as being as active as that in the liver, when corrected for organ mass. In patients with chronic renal failure, overall hepatic enzyme metabolism is decreased by anywhere from 26% to 71%. In vitro studies have demonstrated impaired function of CYP3A4 and 2C9 isozymes, whereas 1A2, 2C19 and 2D6 were not affected. Reversible drug metabolism may be affected by chronic renal disease when normal enzyme function is disrupted. The accumulation of uremic toxins has also been associated with a decreased CYP activity. Therefore, patients with severe renal insufficiency receiving chronic drug therapy may experience accumulation of metabolites of some agents as well as the parent compounds.