Enzyme inhibition occurs when other substances reduce the synthesis and activity of enzymes, thereby reducing the rate of metabolism for drugs involving those enzymes. There are four mechanisms by which inhibition of a CYP can occur.
- Competitive inhibition: A drug and an inhibitor (another drug or xenobiotic) are very similar in structure and affinities for the same CYP active site.
- Non-competitive inhibition: The inhibitor and drug are not competing for the same active site on the enzyme, but there is a different site (allosteric site) that when the inhibitor binds to, the conformation of the active site is changed, preventing the drug from binding to the active site.
- Uncompetitive inhibition: After the drug binds to the enzyme forming the enzyme/substrate complex, the inhibitor binds to the complex, rendering it non-functional. This mechanism is rare.
- Mechanism-based or metabolism-dependent inhibition: Conversion of the drug to a metabolite that is a more potent inhibitor. For example, the furanocoumarin compounds in grapefruit juice are potent inhibitors of CYP3A4.
Assessing any drug interaction can be very complicated for patients taking several medications. Many prescription drugs can inhibit the CYP enzymes. Inhibition can cause the accumulation of the active parent drug in the body to toxic levels and possibly death. In the case of prodrugs, a decrease in metabolism will result in decreased potency of the parent drug.
Inhibition is a significant cause of drug-drug interactions. It results from either the competition between two drugs metabolized by the same enzyme or the CYP converts the drug to a metabolite that is a more potent inhibitor than the parent compound. In other words, an inhibitor can be either the parent drug or its reactive metabolite.
In contrast to enzyme induction, inhibition can have much more severe consequences. The drug's effects are greatly amplified. The consequences of drugs with a wide therapeutic range may not be severe. However, the results can be deadly in medications with a narrow therapeutic range.
Cimetidine, carbamazepine, and theophylline are other examples of drug-drug interactions mediated by effects at CYPs. Cimetidine blocks the P450 pathway and slows down theophylline metabolism, resulting in a longer half-life and higher plasma levels. Cimetidine reduces the metabolism of theophylline, resulting in increased serum concentration. Carbamazepine increases the metabolism of theophylline, resulting in decreased serum concentration. Theophylline toxicity can be treated with beta-blockers.
