Enzyme Inhibition

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The page below is a sample from the LabCE course Drug Metabolism. Access the complete course and earn ASCLS P.A.C.E.-approved continuing education credits by subscribing online.

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Enzyme Inhibition

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: Drug and inhibitor (another drug or xenobiotic) are very similar in structure and have similar affinities for the same CYP active site.
  • Non-competitive inhibition: 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 it the conformation of the active site is changed, preventing the binding of the drug to the active site.
  • Uncompetitive inhibition: After the drug binds to the enzyme forming the enzyme/substrate complex, the inhibitor binds to the complex and renders it non-functional. This mechanism is rare.
  • Mechanism-based or metabolism-dependent inhibition: Conversion of drug to a metabolite that is a more potent inhibitor. For example, the furanocoumarin compounds found in grapefruit juice are potent inhibitors of CYP3A4.
For patients taking several medications, assessing any drug interaction can be very complicated. There are many prescription drugs that can inhibit the CYP enzymes. Inhibition can be responsible for the accumulation of 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 major 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 effects of the drug are greatly amplified. The consequences in relation to drugs with a wide therapeutic range may not be severe. However, in drugs with a narrow therapeutic range, the results can be deadly.
Other examples of drug-drug interactions that are mediated by effects at CYPs include examples such as cimetidine, carbamazepine and theophylline. Cimitidine blocks the P450 pathway and slows down theophylline metabolism resulting in a longer half-life and higher plasma levels. Cimetidine reduces metabolism of theophylline resulting in increased serum concentration. Carbamazepine increases metabolism of theophylline resulting in decreased serum concentration. Theophylline toxicity can be treated with beta blockers.