The enzymatic basis of drug-drug interactions with systemic triazole antifungals.
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.
Nivoix
Yasmine
Y
Pôle Pharmacie-Pharmacologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Levêque
Dominique
D
Herbrecht
Raoul
R
Koffel
Jean-Claude
JC
Beretz
Laurence
L
Ubeaud-Sequier
Genevieve
G
D000935:Antifungal Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase