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Cited by 148Pharmacogenetics and Drug MetabolismAdrenal and Paraganglionic TumorsAdrenal Hormones and Disorders

Drug interactions with mitotane by induction of CYP3A4 metabolism in the clinical management of adrenocortical carcinoma: CYP3A4 induction by mitotane

Kroiss, Matthias, Quinkler, Marcus, Lutz, Werner K., Allolio, Bruno, Fassnacht, Martin·2011·Clinical Endocrinology
DOI 10.1111/j.1365-2265.2011.04214.x
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Abstract

Mitotane [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane, (o,p'-DDD)] is the only drug approved for the treatment for adrenocortical carcinoma (ACC) and has also been used for various forms of glucocorticoid excess. Through still largely unknown mechanisms, mitotane inhibits adrenal steroid synthesis and adrenocortical cell proliferation. Mitotane increases hepatic metabolism of cortisol, and an increased replacement dose of glucocorticoids is standard of care during mitotane treatment. Recently, sunitinib, a multityrosine kinase inhibitor (TKI), has been found to be rapidly metabolized by CYP3A4 during mitotane treatment, indicating clinically relevant drug interactions with mitotane. We here summarize the current evidence concerning mitotane-induced changes in hepatic monooxygenase expression, list drugs potentially affected by mitotane-related CYP3A4 induction and suggest alternatives. For example, using standard doses of macrolide antibiotics is unlikely to reach sufficient plasma levels, making fluoroquinolones in many cases a superior choice. Similarly, statins such as simvastatin are metabolized by CYP3A4, whereas others like pravastatin are not. Importantly, in the past, several clinical trials using cytotoxic drugs but also targeted therapies in ACC yielded disappointing results. This lack of antineoplastic activity may be explained in part by insufficient drug exposure owing to enhanced drug metabolism induced by mitotane. Thus, induction of CYP3A4 by mitotane needs to be considered in the design of future clinical trials in ACC.

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Crossref · 10.1111/j.1365-2265.2011.04214.x

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  • Common drugs metabolized by CYP3A4 include statins, opiates, benzodiazepines, warfarin, and some antibiotics.

    “Common drugs metabolized by this enzyme are statins, opiates, benzodiazepines, warfarin, and some antibiotics (for a complete list see Ref. 301).”

    From Adrenocortical carcinoma (2014) · cites this paper as [301]

  • Mitotane is a very strong inducer of the drug-metabolizing microsomal liver and gut enzyme CYP3A4.

    “It has recently become clear that mitotane is a very strong inducer of the drug-metabolizing microsomal liver and gut enzyme CYP3A4 (299, 301–303).”

    From Adrenocortical carcinoma (2014) · cites this paper as [301]

  • The reasons for the negative effect of mitotane on sunitinib response are induction of CYP3A4 by mitotane and metabolism of sunitinib by the same enzyme.

    “The reasons for these findings are induction of CYP3A4 by mitotane and metabolism of sunitinib by the same enzyme (301, 304).”

    From Adrenocortical carcinoma (2014) · cites this paper as [301]

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Authors
Kroiss, M., Quinkler, M., Lutz, W. K., Allolio, B., & Fassnacht, M.
Affiliations
  • University of Würzburg (DE)
  • Charité – Universitätsmedizin Berlin (DE)
Corresponding author
Kroiss, Matthias
ORCID
Venue
Clinical Endocrinology
Publisher
Wiley
Published
2011-10-04
Volume
75
Issue
5
Pages
585-591
ISSN
0300-0664 (ISSN-L)
DOI
10.1111/j.1365-2265.2011.04214.x
OpenAlex
W1606582049
Cited by
148
References
77
Citations by year
2026: 3 · 2025: 15 · 2024: 9 · 2023: 5 · 2022: 10 · 2021: 8 · 2020: 10 · 2019: 7 · 2018: 9 · 2017: 6 · 2016: 8 · 2015: 16 · 2014: 13 · 2013: 14 · 2012: 12
FWCI
1.94
Type
journal article
Language
en
Open access
closed
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 1428 d)
Locations
  • Clinical Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Deutsche Forschungsgemeinschaft
  • Deutsche Krebshilfe
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
mitotane, adrenocortical carcinoma, drug interactions, CYP3A4 induction, sunitinib, hepatic drug metabolism, glucocorticoid replacement therapy, macrolide antibiotics, fluoroquinolones, statins, simvastatin, pravastatin, targeted therapy, glucocorticoid excess
MeSH terms
Sunitinib, Animals, Antineoplastic Agents, Drug Interactions, Humans, Indoles, Mitotane, Pyrroles, Adrenocortical Carcinoma, Cytochrome P-450 CYP3A

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