Inhibitory effects of macrolide antibiotics on cytochrome P450 3A4 by human liver microsomes

Background & Objectives : Macrolide antibiotics have been reported to cause several drug interactions with co-administered drugs clinically. However, there is no clear demonstration to reveal the relative potential to cause drug interaction. Therefore we investigated and compared the inhibitory effects of macrolide antibiotics on cytochrome P450 3A4 (CYP3A4)-catalyzed reactions using human liver microsomes. Methods : Macrolide antibiotics including azithromycin, clarithromycin, dirithromycin, erythromycin, and troleandomycin was co-incubated with midazolam or testosterone, probe substrates of CYP3A4, in human liver microsomes, respectively. Metabolic activities of midazolam 1-hydroxylation and testosterone 6β-hydroxylation were determined using high-performance liquid chromatography and inhibitory effects of macrolide antibiotics were determined by the calculation of IC₅₀ (the concentration of inhibitor representing 50% inhibitory potency) values by nonlinear regression method. Results : Among macrolide antibiotics tested, troleandomycin inhibited midazolam 1-hydroxylation and testosterone 6β-hydroxylation potently with IC ₅₀ values of 52.3 and 65.9 μM, respectively. Clarithromycin and erythromycin showed moderate and similar inhibitory potency on both CYP3A4-catalyzed reactions. However, azithromycin and dirithromycin showed little inhibitory effects on CYP3A4-catalyzed midazolam 1-hydroxylation and testosterone 6β-hydroxylation. Conclusions : Dirithromycin and azithromycin showed little inhibitory effects on CYP3A4-catalyzed reactions. However, other macrolide antibiotics including troleandomycin, clarithromycin, and erythromycin caused significant inhibitory effects, thereby it should be cautious to co-medicated these drugs with other CYP3A4 substrates that have a narrow therapeutic range or concentration-dependent toxicity.