Ketoconazole at high oral doses has been used to lower cortisol in Cushing syndrome. The mechanism responsible is:
- A Inhibition of multiple cytochrome P450 enzymes required for adrenal steroid biosynthesis ✓
- B Blockade of the glucocorticoid receptor
- C Enhanced hepatic metabolism of cortisol through CYP3A4 induction
- D Selective inhibition of 11-beta hydroxysteroid dehydrogenase type 2
Correct answer: A. Inhibition of multiple cytochrome P450 enzymes required for adrenal steroid biosynthesis
Explanation
Ketoconazole is a nonspecific inhibitor of several cytochrome P450 enzymes, including cholesterol side-chain cleavage enzyme, 17-alpha hydroxylase and 11-beta hydroxylase, thereby blocking cortisol synthesis in the adrenal cortex. The effect is dose dependent and unrelated to its antifungal ergosterol action at usual topical doses. It does not block the glucocorticoid receptor, which is mifepristone's target, and it inhibits rather than induces CYP3B4. Hepatotoxicity limits its use as a steroidogenesis inhibitor.
Reference: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 14th ed.
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