This isoform may account for more than 50% of all CYP-mediated drug oxidation reactions, and CYP3A4 is likely to be involved in the greatest number of drug-drug interactions. The active site of CYP3A4 is thought to be large relative to other isoforms, as evidenced by its ability to accept substrates up to a molecular weight of 1200 (e.g., cyclosporine). This active site size allows drugs with substantial variation in molecular structure to bind within the active site. However, the fact that two drugs are metabolized predominantly by CYP3A4 does not mean that coadministration will result in a drug-drug interaction, since drugs can bind in different regions of the CYP3A4 active site, and these binding regions may be distinct. In fact, it is believed that two drugs (substrates) can occupy the active site simultaneously, with both available for metabolism by the enzyme. This finding helps account for a number of absent interactions that would have been predicted to occur based on strict substrate specificity rules.
CYP3A5, whose amino acid sequence is similar to that of CYP3A4, appears to possess roughly the same substrate specificity characteristics as CYP3A4. However, it differs in that it is not present in all individuals. Thus, patients expressing both CYP3A4 and CYP3A5 have the potential to exhibit increased metabolism of CYP3A substrates as compared to individuals expressing only the CYP3A4 isoform.
Levels of CYP enzyme expression of any isoform can vary substantially among individuals. The other identified human CYP3A isoform is CYP3A7, which appears to be expressed only in the fetus and rapidly disappears following birth, to be replaced by CYP3A4 and CYP3A5. It is becoming increasingly clear that different enzyme expression patterns, and thus different drug metabolism capabilities, are observed throughout the various stages of life. Neonates are different from 6-month-old infants, who differ from year-old infants, who differ from preadolescents, who differ from adolescents, who differ from adults, who differ from the elderly. Thus, consideration must be given to the person's age when assessing drug metabolism capacity.
The second most common CYP isoform involved in human drug metabolism is CYP2D6. It may account for 30% of the CYP-mediated oxidation reactions involving drugs, including the metabolism of drugs in such diverse therapeutic categories as antipsychotic agents, tricyclic antidepressants, p-blocking agents, and opioid analgesics. Though this isoform accepts a number of drugs as substrates, its relative abundance in the liver is quite low. CYP2D6 is most known for its propensity to exhibit genetic polymorphisms (see Pharmacogenetics, later in the chapter).
The other isoform responsible for a substantial portion (about 10%) of the CYP-mediated drug oxidation
TABLE 4.2 Representative Drugs Metabolized by Each of the CYP Isoforms in Human Drug Metabolism
CYP Isoform Examples of Substrates
CYP1A1 Essentially same as CYP1A2
CYP1A2 Polycyclic aromatic hydrocarbons, caffeine, theophylline
CYP2A6 Nicotine, 5-fluorouracil, coumarin
CYP2B6 Bupropion, cyclophosphamide, propofol
CYP2C9 Phenytoin, warfarin, nonsteroidal antiinflammatory drugs
CYP2D6 Tricyclic antidepressants, codeine, dextromethorphan, some ß-blockers, some antipsychotics, some antiarrhythmics
CYP2E1 Acetaminophen, chlorzoxazone
CYP3A4 Midazolam, triazolam, cyclosporine, erythromycin, HIV protease inhibitors, calcium channel blockers
CYP3A5 Essentially same as CYP3A4
CYP3A7 Unclear but may be similar to CYP3A4
Polymorphic Polymorphic Polymorphic
Polymorphic Present only in the fetus
CYP, cytochrome P450.
reactions is CYP2C9. This isoform metabolizes several clinically important drugs with narrow therapeutic indices. Two of these drugs are the antiepileptic agent phenytoin and the anticoagulant warfarin. Any change in the metabolism of these two drugs, either increased or decreased, can have profound adverse effects. CYP2C9 appears to prefer weakly acidic drugs as substrates, which limits the number of drugs metabolized by this isoform, since most drugs are weak bases).
The remaining CYP isoforms involved in human drug metabolism (Table 4.2) are present in the liver in varying amounts, and each is thought to contribute 2-3% or less of the CYP-mediated drug oxidation reactions. Though they may not be involved in the metabolism of a broad range or significant number of drugs, if they are the primary enzyme responsible for the metabolism of the drug of interest, then their importance in that instance is obviously increased.
CYP450 enzymes can be regulated by the presence of other drugs or by disease states. This regulation can either decrease or increase enzyme function, depending on the modulating agent. These phenomena are commonly referred to as enzyme inhibition and enzyme induction, respectively.
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