(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.
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
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.
- Clarithromycin (Biaxin) product package insert. North Chicago, IL. Version: August 2009.
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.
S, Yung Chan S, Cher Goh B et al. Mechanism-based inhibition of
cytochrome P450 3A4 by therapeutic drugs. Clin Pharmacokinet
M, Descatoire V, Larrey D et al. Effects of clarithromycin on
cytochrome P-450. Comparisons with other macrolides. J Pharmacol Exp
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
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.
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.
B, Lopez de Ocariz A et al. Concurrent clarithromycin and cyclosporin A
treatment. J Antimicrob Chemother 1998;42:393-5.
DJ, von Moltke LL, Harmatz JS et al. Inhibition of triazolam clearance
by macrolide antimicrobial agents: in vitro correlates and dynamic
TA. Comparative pharmacokinetic interaction profiles of pravastatin,
simvastatin, and atorvastatin when coadministered with cytochrome P-450
inhibitors. Am J Cardiol 2004;94:1140-6.