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.
Department of Pharmaceutical and Medicinal Chemistry, Universitätscampus C2.3, 66123 Saarbrücken, Germany.
J Steroid Biochem Mol Biol. 2020 May;199:105605. doi: 10.1016/j.jsbmb.2020.105605. Epub 2020 Jan 23.
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.
近期报道描述了在使用泊沙康唑和伊曲康唑进行抗真菌治疗期间出现严重高血压和低钾血症，同时伴有低肾素和醛固酮水平的病例。这些情况代表了由盐皮质激素过多引起的继发性内分泌性高血压的特征。不同的机制可导致盐皮质激素过多，包括抑制肾上腺甾体生成酶 CYP17A1 和 CYP11B1、抑制外周皮质醇氧化酶 11β-羟类固醇脱氢酶 2（11β-HSD2）或直接激活盐皮质激素受体（MR）。与先前的实验结果相比，伊曲康唑对 11β-HSD2 的抑制作用比泊沙康唑强三倍，而本研究发现泊沙康唑对 CYP11B1 的抑制作用比伊曲康唑强七倍。两种化合物对 CYP11B2 的抑制作用最强。主要的具有药理活性的伊曲康唑代谢物羟基伊曲康唑（OHI）与伊曲康唑的作用相似，但活性要低得多。分子建模计算评估了泊沙康唑、伊曲康唑和 OHI 与 11β-HSD2 和相关 CYP 酶的结合情况，并预测了其他系统使用的唑类抗真菌药物未形成的重要相互作用，从而为观察到的抑制活性提供了初步解释。结合现有临床观察结果，所提供的数据表明，伊曲康唑主要通过抑制 11β-HSD2 导致皮质醇诱导的 MR 激活引起假性醛固酮增多症，而泊沙康唑则通过 CYP11B1 抑制和促肾上腺皮质激素释放激素-垂体-肾上腺轴（HPA）反馈激活导致 11-脱氧皮质酮和 11-脱氧皮质醇等盐皮质激素的积累引起。治疗药物监测和引入较高的血浆靶水平可能有助于预防药物引起的高血压和低钾血症的发生。此外，系统使用的唑类抗真菌药物伏立康唑、艾沙康唑和氟康唑均不影响任何盐皮质激素过多的靶点，为治疗提供了替代选择。
