I thank Dr Goodchild for his interest and thoughtful comment about my article concerning the coadministration of triazolam with azithromycin.1 This coadministration is not well defined in the literature. Biotransformation of these drugs is performed by the hepatic or intestinal cytochromes P450, the mixed-function oxidase system. CYP 3A4 is within this system and is responsible for action on triazolam. Several references lump all the macrolides together and warn of potentiation by inhibiting the oxidative biotransformation by CYP 3A4 of triazolam in coadministration.
Macrolides inhibit CYP 3A4 by being transformed into nitrosoalkanes that, with iron, form an inactive CYP 3A4 comples, thus inhibiting biotransformation and increasing the plasma concentrations and prolonging the half-life of triazolam. This reaction produces most of the interactions by macrolides. However, azithromycin may be an exception. Westphal2 cites Greenblatt et al,3 saying that azithromycin is a weak inhibitor of triazolam biotransformation, whereas erythromycin and clarithromycin are potent inhibitors and azithromycin produces “no effect on the kinetics or dynamics or triazolam.” Pai et al4 agree that azithromycin produces “few clinically significant interactions with any agent cleared through the cytochrome P450 enzyme system.”
However, Drug Facts and Comparisons5 and Mosby's Drug Consult6 specifically mention azithromycin as contraindicated for coadministration with triazolam. The websites accessmednet.com and efactsonline.com also specifically mention azithromycin. (These references do not list citations.) There is also a question that arises about the in vitro method of drug investigation. There are uncertainties regarding nonspecific microsomal binding, solvent effects on enzyme activity, and estimations of enzyme-available inhibitor concentrations.7 Because this issue is not well defined, I chose to state in my article that “macrolide antibiotics (such as erythromycin and azithromycin) … may cause increased plasma concentration” and to include the category macrolides in the contraindicated column in the table.
Dr Goodchild's concern is well founded; however, the coadministration of triazolam and azithromycin is not well defined and needs elucidation. Therefore, the practioner should be aware of potential interactions and be prepared for such.