Format

Send to

Choose Destination
J Steroid Biochem Mol Biol. 2020 Jan 23;199:105605. doi: 10.1016/j.jsbmb.2020.105605. [Epub ahead of print]

Molecular mechanisms of posaconazole- and itraconazole-induced pseudohyperaldosteronism and assessment of other systemically used azole antifungals.

Author information

1
Swiss Centre for Applied Human Toxicology (SCAHT) and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: katharina.beck@unibas.ch.
2
Swiss Centre for Applied Human Toxicology (SCAHT) and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: lucija.telisman@gmx.at.
3
Department of Pharmaceutical and Medicinal Chemistry, Universitätscampus C2.3, 66123 Saarbrücken, Germany. Electronic address: vankoppen@elexopharm.de.
4
Department of Internal Medicine, Division of Infectious Diseases, University of California Davis Medical Center, Davis, California, USA. Electronic address: grthompson@ucdavis.edu.
5
Swiss Centre for Applied Human Toxicology (SCAHT) and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: alex.odermatt@unibas.ch.

Abstract

Recent reports described cases of severe hypertension and hypokalemia accompanied by low renin and aldosterone levels during antifungal therapy with posaconazole and itraconazole. These conditions represent characteristics of secondary endocrine hypertension caused by mineralocorticoid excess. Different mechanisms can cause mineralocorticoid excess, including inhibition of the adrenal steroidogenic enzymes CYP17A1 and CYP11B1, inhibition of the peripheral cortisol oxidizing enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) or direct activation of the mineralocorticoid receptor (MR). Compared to previous experiments revealing a threefold more potent inhibition of 11β-HSD2 by itraconazole than with posaconazole, the current study found sevenfold stronger CYP11B1 inhibition by posaconazole over itraconazole. Both compounds most potently inhibited CYP11B2. The major pharmacologically active itraconazole metabolite hydroxyitraconazole (OHI) resembled the effects of itraconazole but was considerably less active. Molecular modeling calculations assessed the binding of posaconazole, itraconazole and OHI to 11β-HSD2 and the relevant CYP enzymes, and predicted important interactions not formed by the other systemically used azole antifungals, thus providing an initial explanation for the observed inhibitory activities. Together with available clinical observations, the presented data suggest that itraconazole primarily causes pseudohyperaldosteronism through cortisol-induced MR activation due to 11β-HSD2 inhibition, and posaconazole by CYP11B1 inhibition and accumulation of the mineralocorticoids 11-deoxycorticosterone and 11-deoxycortisol because of hypothalamus-pituitary-adrenal axis (HPA) feedback activation. Therapeutic drug monitoring and introduction of upper plasma target levels may help preventing the occurrence of drug-induced hypertension and hypokalemia. Furthermore, the systemically used azole antifungals voriconazole, isavuconazole and fluconazole did not affect any of the mineralocorticoid excess targets, offering alternative therapeutic options.

KEYWORDS:

11beta-hydroxysteroid dehydrogenase; Azole antifungal; CYP11B1; Fluconazole (PubChem CID: 3365); Hydroxyitraconazole (PubChem CID: 108222); Hypertension; Isavuconazole (PubChem CID: 6918485); Itraconazole (PubChem CID: 55283); Ketoconazole (PubChem CID: 47576); Mineralocorticoid receptor; Posaconazole (PubChem CID: 468595); Voriconazole (PubChem CID: 71616)

Conflict of interest statement

Declaration of Competing Interest Chris J. van Koppen was an employee of Elexopharm, Germany. The other authors declare no conflict of interest.

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center