Co-Administration of the CYP3A4 Inhibitor Diltiazem Counteracts Mitotane-Induced Clearance of Glucocorticoids and Antihypertensives in a Patient with Adrenocortical Carcinoma

Objective: We report a case of adrenal insufficiency and resistant hypertension in a patient with adrenocortical cell carcinoma (ACC) under mitotane treatment, in which a cytochrome P450 (CYP)3A4 inhibitor, diltiazem, successfully reduced mitotane-induced clearance of glucocorticoids and antihypertensives. Methods: The patient underwent clinical, biochemical, and radiologic assessment. The urinary 6β-hydroxycortisol (6β-OHF) to cortisol (F) ratio, an index of CYP3A4 activity, was evaluated before and after administration of diltiazem. Results: A 63-year-old woman diagnosed with ACC and Cushing syndrome was treated with mitotane. After several months, she presented signs of adrenal insufficiency, despite adequate glucocorticoid replacement. She developed grade 3 hypertension, although treatment with 5 antihypertensives (amlodipine, eplerenone, olmesartan, carvedilol, and doxazosin) was continued. Her plasma mitotane concentrations were above the therapeutic range, suggesting mitotane-induced, CYP3A4-dependent inactivation of glucocorticoid and the antihypertensives (amlodipine and eplerenone), all of which are known CYP3A4 substrates. Diltiazem, a calcium-channel blocker with an inhibitory effect on CYP3A4, was initiated based on the rationale that it counteracts mitotane-induced CYP3A4-dependent drug interactions. After 7 days, adrenal insufficiency and resistant hypertension improved and were accompanied by a significant reduction in the urinary 6β-OHF:F ratio. Conclusion: This is the first case report demonstrating a counteracting effect of a CYP3A4 inhibitor on mitotane-induced drug interactions in ACC. It also suggests the usefulness of the urinary 6β-OHF:F ratio as a biomarker for CYP3A4 activity during mitotane treatment. Abbreviations: 6β-OHF = 6β-hydroxycortisol ACC = adrenocortical cell carcinoma ACTH = adrenocorticotropic hormone CYP = cytochrome P450 F = cortisol