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

Publication date: Available online 23 January 2020Source: The Journal of Steroid Biochemistry and Molecular BiologyAuthor(s): Katharina R. Beck, Lucija Telisman, Chris J. van Koppen, George R. Thompson, Alex OdermattAbstractRecent 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 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 initia...

Source: The Journal of Steroid Biochemistry and Molecular Biology - January 23, 2020 Category: Biochemistry Source Type: research