Title:Drug Interactions between Nine Antifungal Agents and Drugs Metabolized by Human Cytochromes P450
Volume: 15
Issue: 7
Author(s): Toshiro Niwa, Yurie Imagawa and Hiroshi Yamazaki
Affiliation:
Keywords:
Antifungal agent, azole, cytochrome P450, CYP51 (14α-sterol demethylase), echinocandin, inhibition.
Abstract: This article reviews in vitro metabolic and in vivo pharmacokinetic drug–drug interactions of nine antifungal agents: six azoles
(fluconazole, itraconazole, ketoconazole, miconazole, posaconazole, and voriconazole) and three echinocandins (anidulafungin, caspofungin,
and micafungin). In in vitro interaction studies, itraconazole, ketoconazole, and miconazole were found to have higher inhibitory
effects on cytochrome P450 (P450 or CYP) 3A4 and 3A5 activities than the other azoles or echinocandins did. Fluconazole, itraconazole,
and voriconazole were relatively less potent inhibitors of CYP3A5 than of CYP3A4. The inhibitory effects of fluconazole, itraconazole,
ketoconazole, and voriconazole against CYP3A4 and CYP3A5 seemed to be correlated with their dissociation constants for CYP51 (lanosterol
14α-demethylase) from Candida albicans. In in vivo pharmacokinetic studies, itraconazole was found to be a potent clinically
important inhibitor of CYP3A4/5 substrates, and fluconazole and voriconazole increased the blood/plasma concentrations of not only
CYP3A4/5 substrates but also CYP2C9 substrates. Miconazole was a potent inhibitor of all P450s investigated in vitro, although there
are few detailed studies on the clinical significance of this except for CYP2C9. For the echinocandins, no marked inhibition of P450 activities,
except for some inhibition of CYP3A4/5 activity, was observed in vitro. The blood/plasma concentrations of concomitant drugs
were not markedly affected by coadministration of echinocandins in vivo, suggesting that echinocandins do not cause clinically significant
interactions with drugs that are metabolized by P450s via the inhibition of metabolism. The differential effects of these antifungal
agents on P450 activities must be considered when clinicians select antifungal agents for patients also receiving other drugs.
