Dose- and time-dependent changes in blood and adrenal levels of multiple steroids in rats after administration of ketoconazole with or without ACTH

Abstract

To verify simultaneous measurement of blood levels of adrenal steroids as a tool to evaluate drug effects on adrenal steroidogenesis, dose-and time-dependent changes in blood levels of corticosterone and its precursors (pregnenolone, progesterone and deoxycorticosterone), as well as their relationship with the pathological changes in the adrenal gland, were examined in rats dosed with ketoconazole (KET). Also examined were whether effects on adrenal steroidogenesis that were not obvious in the blood steroid levels after sole administration of KET could be revealed by post-administration of ACTH, and the correlation between the blood and adrenal steroid levels. Male rats were dosed with 15, 50, or 150 mg/kg of KET for 1 or 7 days with or without ACTH, and the blood and adrenal concentrations of the steroids were measured. KET increased the blood deoxycorticosterone level even at a dose level and time point at which histopathological changes were not obvious. KET-induced changes in blood levels of other steroids were revealed by ACTH, and the blood and adrenal levels were generally correlated especially after ACTH post-administration. Thus, blood levels of adrenal steroids, including precursors, can be a sensitive and early marker of drug effects on the adrenal steroidogenesis that reflect adrenal levels of steroids. The usefulness of the multiple steroid measurement as a method for mechanism investigation of drug effects on the adrenal gland can be further enhanced by ACTH.

Spectrophotometric study of ketoconazole binding with citrate capped silver nanoparticles and its monitoring in human plasma samples

“…Moreover, this enzyme plays a critical role in corticosteroid synthesis and metabolism. Therefore, beside antifungal potential, it is one of the few available remedies for Cushing's syndrome . Although this drug is effective in decreasing cortisol and reducing the clinical effects of Cushing's syndrome, it is life‐threatening due to the risk of severe hepatotoxicity …”

“…Therefore, beside antifungal potential, it is one of the few available remedies for Cushing's syndrome. 7 Although this drug is effective in decreasing cortisol and reducing the clinical effects of Cushing's syndrome, it is life-threatening due to the risk of severe hepatotoxicity. 8 Moreover, it has been reported that this antifungal agent is able to induce a variety of heart function side effects, such as long-QT syndrome 9 and ventricular arrhythmias.…”