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What does it mean for a drug to be a mechanism-based inhibitor of cytochrome P-450 (CYP) 3A4?

Summary:

  • It is well known that the cytochrome P-450 (CYP) enzyme system is involved in the drug metabolism of many medications used in clinical practice and have been implicated in causing clinically relevant drug-drug interactions.
  • Mechanism-based inhibition typically results in the irreversible inhibition of CYP3A4, thereby making that enzyme completely nonfunctional until it is replaced with newly synthesized CYP3A4 enzymes. 
  • The irreversible inhibition of CYP3A4 occurs in the middle of metabolizing the medication known to be a mechanism-based inhibitor because of the formation of a metabolite intermediate. 
  • Due to the irreversible inhibition of CYP3A4, and knowing the large number of medications known to depend on this enzyme for their metabolism, the medications known to cause this are associated with clinically relevant drug-drug interactions.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed: August 2015

Explanation

  • It is well known that the cytochrome P-450 (CYP) enzyme system is involved in the drug metabolism of many medications used in clinical practice and have been implicated in causing clinically relevant drug-drug interactions.1,2  There are a number of CYP450 enzymes involved in mediating drug interactions and commonly include CYP1A2, 2C9, 2C19, 2D6, and 3A4.1  Of these CYP enzymes, CYP3A4 is not only the most prevalent CYP enzyme in the liver, but is used by more than 50% of medications on the market for their metabolism and elimination from the body.1  The problem occurs when in the metabolism of these substrates of CYP3A4 also result in the inhibition of CYP3A4.  A number of medications are known to be inhibitors of CYP3A4, but they differ in the degree of inhibition they have on the enzyme and the type of inhibition they confer.1  One type of inhibition of CYP3A4 is mechanism-based inhibition.3 

    Mechanism-based inhibition typically results in the irreversible inhibition of CYP3A4, thereby making that enzyme completely nonfunctional until it is replaced with newly synthesized CYP3A4 enzymes.3  The irreversible inhibition of CYP3A4 occurs during the metabolism of the inhibitor itself.  The medication causing the inhibition of CYP3A4 is also a substrate of CYP3A4 for its metabolism.  The irreversible inhibition of CYP3A4 occurs in the middle of metabolizing the medication known to be a mechanism-based inhibitor because of the formation of a metabolite intermediate.4   These metabolic intermediates can then form covalent bonds with CYP3A4, thereby resulting in the irreversible inhibition of their activity.  Medications known to commonly cause this type of inhibition to CYP3A4 are commonly characterized as having the following moieties associated with the chemical structure: tertiary amine function, furan rings, and acetylene function.3,5-7 

    Due to the irreversible inhibition of CYP3A4, and knowing the large number of medications known to depend on this enzyme for their metabolism, the medications known to cause this are associated with clinically relevant drug-drug interactions.  Examples of medications that are known to be mechanism-based inhibitors include: clarithromycin, delavirdine, diltiazem, erythromycin, and verapamil.3   Understanding the underlying mechanism for this type of inhibition of CYP3A4 can help the clinician to appropriately assess, monitor and avoid drug interactions that would compromise the safety of their patients.

    References:

    1. Rendic S, Ci Carlo FJ.  Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors.   Drug Metab Rev  1997;29:413-580.
    2. United States Food and Drug Administration.  Guidance for Industry.  Drug Interaction Studies - Study Design, Data Analysis, and Implications for Dosing and Labeling.  September 2006. Clinical Pharmacology. Accessed last on 5/19/2009.
    3. Zhou S, Yung Chan S, Cher Goh B et al.  Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs.  Clin Pharmacokinet  2005;44:279-304.
    4. Kent UM, Juschyshyn MI, Holenberg PF.  Mechanism-based inactivators as probes of cytochrome P450 structure and function.  Curr Drug Metab  2001;2:215-43.
    5. Larrey D, Funck-Brentano C, Breil P et al.  Effects of erythromycin on hepatic drug-metabolizing enzymes in humans.  Biochem Pharmacol  1983;32:1063-8.
    6. He K, Iyer KR, Hayes RN et al.  Inactivation of cytochrome P450 3A4 by bergamottin, a component of grapefruit juice.  Chem Res Toxicol  1998;11:252-9.
    7. Guengerich FP.  Mechanism-based inactivation of human liver microsomal cytochrome P-450 IIIA4 by gestodene.  Chem Res Toxicol  1990:3:363-71.

MESH Terms & Keywords

  • Mechanism Based Inhibitor, Cytochrome, CYP450, CYP3A4, CYP, Drug Interactions