临床药物手册( 英文原版)15.pdf

Drug Interactions and Interferences 5 Cytochrome P450 Enzyme Interactions Philip D. Hansten Cytochrome P450 enzymes are found throughout the body and play an important role in the metabolism of many drugs by catalyzing -hydroxylation, N- demethylation, ring oxidation, and more.1,2 Most substrates are metabolized by a specific enzyme, whereas each cytochrome P450 enzyme is generally capable of metabolizing many different compounds.2,3 Induction or inhibition of these en- zymes can dramatically affect the outcome of drug therapy. Cytochrome P450 enzymes are identified by the prefix “CYP” followed by an Arabic number identifying the family, although Roman numerals are still sometimes used. The three important enzyme families in humans are CYP1, CYP2, and CYP3. Subfamilies are given letters (eg, CYP2B, CYP2C) that are fol- lowed by numbers identifying the specific enzyme. Although most concentrated in the liver, cytochrome P450 enzymes exist in all tissues of the human body.2,3 Intestinal mucosal cytochrome P450 enzymes ap- pear to be primarily from the CYP3A family, probably CYP3A4 in humans.3 These enzymes affect the bioavailability of some drugs. INDUCTION AND INHIBITION When the amount of enzyme present in the body is increased by a drug or chemi- cal, the enzyme is said to be “induced.” Although most inducers are P450 sub- strates, this is not always the case. Induction can increase the rate of clearance of a drug, decreasing its efficacy. It also can increase the rate of formation of an active or toxic metabolite, resulting in exaggeration of therapeutic effect or increased toxicity. Theoretically, all substrates metabolized by the same en