The DOI matches its Crossref record; 25 of the 25 references it cites were found in a registry or an index.
Mitotane has a strong and a durable inducing effect on CYP3A4 activity
Abstract
OBJECTIVE: The effects of mitotane on the pharmacokinetics (PK) of co-administered drugs are mostly unknown. The aim of the present study was to describe the effects of mitotane on the PK of the phenotypic probe midazolam and of the tyrosine kinase inhibitor sunitinib. DESIGN: A serendipitous observation was made in two of nine patients who volunteered in a sunitinib pharmacokinetic study. Both patients were diagnosed with adrenocortical carcinoma (ACC) and were exposed to mitotane. The sunitinib PK study was designed to determine the relationship between CYP3A4 activity and sunitinib exposure using 7.5 mg midazolam orally as a phenotypic probe. Patient and methods Serial blood samples for PK analysis of midazolam, 1-hydroxy-midazolam, and sunitinib were collected at steady-state sunitinib PK (between days 14 and 20). To confirm this observation in the mitotane-exposed patients, midazolam PK was evaluated in two additional patients with ACC and mitotane treatment. RESULTS: The four mitotane-treated patients showed highly induced CYP3A4 activity, even after interrupting mitotane therapy months before study entry, reflected by decreased midazolam exposure compared with the other seven patients (mean AUC(0)(-)(12 h) (95% CI): 7.6 (5.5-9.7) vs 139.0 (95.1-182.9) μg×h/l respectively P=0.001) and increased 1-hydroxy-midazolam exposure (mean AUC(0)(-)(12 h) (95% CI): 409.6 (290.5-528.7) vs 35.0 (26.4-43.6) μg×h/l, P=0.008). Sunitinib exposure was decreased in the two patients who were co-treated with mitotane (267 and 268 μg×h/l versus 1344 (1079-1609) (mean (95% CI)) μg×h/l). CONCLUSION: Mitotane has a strong and long-lasting inducing effect on CYP3A4 activity, which will result in clinically relevant interactions with multiple drugs since many drugs are metabolized by this enzyme.
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“A study using sunitinib, which is metabolized by CYP3A4, raised concerns that several of the study subjects did not reach therapeutic levels of this drug (302, 304).”
From Adrenocortical carcinoma (2014) · cites this paper as [302]
In the citing paper
“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 [302]
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Metadata
- Authors
- van Erp, N. P., Guchelaar, H.-J., Ploeger, B. A., Romijn, J. A., Hartigh, J. D., & Gelderblom, H.
- Affiliations
- Leiden University Medical Center (NL)
- Venue
- European Journal of Endocrinology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-04
- Volume
- 164
- Issue
- 4
- Pages
- 621-626
- ISSN
- 0804-4643 (ISSN-L)
- 1479-683X
- OpenAlex
- W2142711036
- Cited by
- 118
- References
- 25
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 6 · 2023: 4 · 2022: 14 · 2021: 7 · 2020: 9 · 2019: 7 · 2018: 5 · 2017: 7 · 2016: 6 · 2015: 12 · 2014: 6 · 2013: 11 · 2012: 14
- FWCI
- 11.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Keywords
- mitotane, CYP3A4 induction, midazolam, sunitinib, drug-drug interactions, adrenocortical carcinoma, pharmacokinetics, midazolam hydroxylation, tyrosine kinase inhibitors
- MeSH terms
- Sunitinib, Adult, Aged, Antineoplastic Agents, Enzyme Activation, Female, Humans, Indoles, Male, Middle Aged, Mitotane, Pyrroles, Adrenocortical Carcinoma, Cytochrome P-450 CYP3A
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