Effect of dirithromycin on human CYP3A in vitro and on pharmacokinetics and pharmacodynamics of terfenadine in vivo.

Terfenadine is metabolized by the cytochrome P-450 3A subfamily of enzymes (CYP3A). Certain macrolide antibiotic agents inhibit CYP3A and, when coadministered with terfenadine, result in a drug interaction. The authors compared the abilities of dirithromycin (a new macrolide antibiotic agent), its major metabolite erythromycylamine, and the known CYP3A substrate terfenadine to inhibit CYP3A in vitro. The hydroxylation of midazolam in human liver microsomes was used as a probe for CYP3A activity. Dirithromycin and erythromycylamine were low affinity inhibitors of CYP3A (inhibitory binding affinities of 493 mumol/L and 701 mumol/L, respectively); conversely, terfenadine was a moderate affinity inhibitor (inhibitory binding affinity of 28 mumol/L). Based on these data, the authors tested the hypothesis that dirithromycin would not interact with terfenadine in humans. Six healthy men received terfenadine alone (60 mg twice daily) for 8 days, after which dirithromycin (500 mg once daily) was added to the terfenadine regimen for an additional 10 days. The pharmacokinetics of terfenadine (and its acid metabolite) and the QTc interval were measured during both treatments, and it was found that neither parameter was affected. In this study, dirithromycin was found to have low affinity for human CYP3A in vitro, which is in accordance with the study's finding that in vivo dirithromycin has no major effect on the metabolism of the CYP3A substrate terfenadine in humans.