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Clarithromycin's (Biaxin) Inhibition of CYP450 3A4

Summary:

  • Clarithromycin (Biaxin) is a well known macrolide antibiotic used in the management of Helicobacter pylori, uncomplicated skin, and upper and lower respiratory tract infections.
  • Unfortunately, clarithromycin can cause drug interactions because of its ability to inhibit the cytochrome P450 (CYP) 3A4 enzyme.
  • Clarithromycin inhibits CYP3A4 activity by an irreversible mechanism-based inhibition which occurs when it is metabolized by CYP3A4 to form reactive a nitrosoalkane via N-demethylation.  This metabolite intermediate then covalently interacts with CYP3A4 to form metabolite intermediate complex rendering it inactive until replaced with new enzyme.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Reviewer:
Jon D. Herrington, PharmD, BCPS, BCOP
Last Reviewed:
August 2015

Explanation

  • Clarithromycin (Biaxin) is a well known macrolide antibiotic used in the management of Helicobacter pylori, uncomplicated skin, and upper and lower respiratory tract infections.1  Unfortunately, clarithromycin can cause drug interactions because of its ability to inhibit the cytochrome P450 (CYP) 3A4 enzyme.  In regard to the CYP enzyme system as a whole, it is widely understood to be involved in the metabolism of many medications used in clinical practice and has been implicated in many clinically relevant drug-drug interactions.2,3  There are a number of CYP450 enzymes that mediate drug interactions and these frequently include CYP1A2, 2C9, 2C19, 2D6, and 3A4.2  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.2  As such, any inhibitor of CYP3A4 can put patients at increased risk for side effects and/or adverse drug events from medications that require CYP3A4 for their metabolism. 

    The type and degree of enzyme inhibition can also influence the potential for these unwanted reactions to occur.  Inhibitors of such enzymatic reactions elicit their effects through competitive, noncompetitive, reversible, and irreversible antagonism.  Irreversible antagonism can also include mechanism-based inhibition.  In fact, this is the type of inhibition clarithromycin exerts on CYP3A4.   This type of inhibition comes about from the activity of CYP3A4's which facilitates the inactivation of the drug that relies upon CYP3A4.3  This reaction generates a metabolic intermediate which covalently bonds to the same enzyme and facilitates its inactivation.3  Specific to clarithromycin, it can be metabolized by CYP3A4 to form reactive a nitrosoalkane via N-demethylation which then interacts with CYP3A4 to form metabolite intermediate complex.4,5  Since the formation of a metabolite intermediate can occur with clarithromycin, the more clarithromycin given the greater the degree of overall inhibition on CYP3A4 because of the additional formation of metabolite intermediates that can further inhibit CYP3A4 activity.6 

    The irreversible mechanism-based inhibition of CYP3A4 can be overcome with the replacement of newly formed enzyme, however, this can take longer than 12-24 hours to regenerate.  While this is obviously not an exhaustive list of known drug interactions, this type of inhibition is known to be the reason for clarithromycin's ability to increase the steady state concentrations of cisapride and cyclosporine by 3.2 and 2-3 fold, respectively, to increase the area under of the curve (AUC) concentrations of simvastatin and atorvastatin 10 and 4 fold, respectively, and to reduce the clearance of triazolam by 4.3 fold.7-10.

    References:

    1. Clarithromycin (Biaxin) product package insert.  North Chicago, IL.  Version: August 2009.
    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. Tinel M, Descatoire V, Larrey D et al.  Effects of clarithromycin on cytochrome P-450.  Comparisons with other macrolides.  J Pharmacol Exp Ther  1989;250:746-51.
    5. Delaforge M, Jaouen M, Mansuy D.  Dual effects of macrolide antibiotics on rat liver cytochrome P-450.  Induction and formation of metabolite-complexes: a structure-activity relationship.  Biochem Pharmacol  1983;32:2309-18.
    6. Mayhew BS, Jones DR, Hall SD.  An in vitro model for predicting in vivo inhibition of cytochrome P450 3A4 by metabolic intermediate complex formation.  Drug Metab Dispos  2000;28:1031-7.
    7. Van Haarst AD, van 't Klooster GA, van Gerven JM et al.  The influence of cisapride and clarithromycin on QT intervals in healthy volunteers.  Clin Pharmacol Ther  1998;64:542-6.
    8. Sadaba B, Lopez de Ocariz A et al.  Concurrent clarithromycin and cyclosporin A treatment.  J Antimicrob Chemother  1998;42:393-5.
    9. Greenblatt DJ, von Moltke LL, Harmatz JS et al.  Inhibition of triazolam clearance by macrolide antimicrobial agents: in vitro correlates and dynamic consequences.  1998;64:278-85.
    10. Jacobson TA.  Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P-450 inhibitors.  Am J Cardiol  2004;94:1140-6.