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The Enzymatic Basis of Drug-Drug Interactions with Systemic Triazole Antifungals

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Abstract

Drug-drug interactions are a recurring problem in immunocompromised patients treated with triazole antifungals. While the introduction of new antifungals has expanded opportunities for lowering drug toxicity, virtually all antifungal regimens carry the risk of pharmacokinetic and pharmacodynamic interaction. This review presents the published data on molecular determinants (enzymes, transporters, orphan nuclear receptors) of systemic triazole pharmacokinetics in humans, including itraconazole, fluconazole, voriconazole and posaconazole. Systemic triazoles are inhibitors of cytochrome P450 (CYP) isozymes, such as CYP3A4, CYP2C9 and CYP2C19, to varying degrees. In addition, some are substrates and/or inhibitors of drug transporters such as multidrug resistance-1 gene product, P-glycoprotein, or breast cancer resistance protein. The interactions of triazole antifungals can be divided into the following categories: modifications of antifungal pharmacokinetics by other drugs, modifications of other drug pharmacokinetics by antifungals, and two-way interactions. These features are the basis of most interactions that occur during triazole therapy.

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Acknowledgements

No sources of funding were used to assist in the preparation of this review. Raoul Herbrecht has received grant support from Pfizer and has served as a consultant for Gilead, Pfizer, Schering-Plough, Merck Sharp and Dohme, Astellas and Novartis. The other authors have no conflicts of interest that are directly relevant to the content of this review.

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Authors and Affiliations

  1. Pôle Pharmacie-Pharmacologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

    Yasmine Nivoix, Dominique Levêque, Jean-Claude Koffel & Laurence Beretz

  2. Pôle d’Oncologie et d’Hématologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

    Raoul Herbrecht

  3. Laboratoire de Biomolécules, Biotechnologie et Innovation Thérapeutique, Faculté de Pharmacie, Université Louis Pasteur, Strasbourg, France

    Genevieve Ubeaud-Sequier

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Nivoix, Y., Levêque, D., Herbrecht, R. et al. The Enzymatic Basis of Drug-Drug Interactions with Systemic Triazole Antifungals. Clin Pharmacokinet 47, 779–792 (2008). https://doi.org/10.2165/0003088-200847120-00003

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