Association of mitotane with chylomicrons and serum lipoproteins: practical implications for treatment of adrenocortical carcinoma

Kroiß, Matthias; Plonné, Dietmar; Kendl, Sabine; Schirmer, Diana; Ronchi, Cristina L.; Schirbel, Andreas; Zink, Martina; Lapa, Constantin; Klinker, Hartwig; Faßnacht, Martin; Heinz, Werner; Sbiera, Silviu

doi:10.1530/eje-15-0946

Cited by 23 publications

(41 citation statements)

References 45 publications

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“…For the monolayer culture, there was no significant difference in cytotoxicity between MT in EtOH and MT in micelles ( p > 0.05) upon 24 h incubation ( Figure 5 a). The IC 50,24h were 15 and 19 µ m for MT in EtOH and micelles, respectively, which corresponds well with values found in the literature (IC 50,24h = 15 µ m . The cell viability was less than 3% at 50 µ m MT concentration (either in EtOH or micelles) consistent with the previous reports by Silveira et al and others .…”

Section: Resultssupporting

confidence: 91%

“…Even at high cumulative doses of 4 to 6 g per day for a consecutive of 3 months, more than half of the patients do not achieve targeted plasma concentration . Overall, MT pharmacokinetics exhibit large inter‐individual variability which appears to be due in part due intestinal and/or hepatic metabolism . The inactive metabolite o,p′‐DDA is also found ten times higher in blood than the active parent compound MT .…”

Section: Introductionmentioning

confidence: 99%

“…Lipophilicity of MT has been shown to result in predominant association with serum lipoproteins (LPs) and also chyle but only free MT was demonstrated to be therapeutically active . Collectively, poor aqueous solubility and difficult to predict PK profile of MT are the major obstacles in MT therapy.…”

Section: Introductionmentioning

confidence: 99%

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A Micellar Mitotane Formulation with High Drug‐Loading and Solubility: Physico‐Chemical Characterization and Cytotoxicity Studies in 2D and 3D In Vitro Tumor Models

Haider

Schreiner

Kendl

et al. 2019

Macromolecular Bioscience

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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A Micellar Mitotane Formulation with High Drug‐Loading and Solubility: Physico‐Chemical Characterization and Cytotoxicity Studies in 2D and 3D In Vitro Tumor Models

Haider

Schreiner

Kendl

et al. 2019

Macromolecular Bioscience

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“…6 and Supplementary Tables 5, 6). Prior studies (46,47) suggested that mitotane cytotoxicity may be influenced by cholesterol-bearing lipoproteins such as LDL and HDL. In the presence of artificially low lipoprotein levels (0.005 mg/mL HDL, 0.005 mg/mL LDL), median IC 50 of not only nonresistant but also resistant cells dropped significantly compared to more physiological levels (0.05 mg/mL HDL, 0.05 mg/mL LDL) ( Supplementary Fig.…”

Section: Mitotane-resistant Cells Show Profoundly Altered Intracellulmentioning

confidence: 99%

Generation and characterization of a mitotane-resistant adrenocortical cell line

Seidel

Walenda

Messerschmidt

et al. 2020

Endocrine Connections

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Mitotane is the only drug approved for the therapy of adrenocortical carcinoma (ACC). Its clinical use is limited by the occurrence of relapse during therapy. To investigate the underlying mechanisms in vitro, we here generated mitotane-resistant cell lines. After long-term pulsed treatment of HAC-15 human adrenocortical carcinoma cells with 70 µM mitotane, we isolated monoclonal cell populations of treated cells and controls and assessed their respective mitotane sensitivities by MTT assay. We performed exome sequencing and electron microscopy, conducted gene expression microarray analysis and determined intracellular lipid concentrations in the presence and absence of mitotane. Clonal cell lines established after pulsed treatment were resistant to mitotane (IC50 of 102.2 ± 7.3 µM (n = 12) vs 39.4 ± 6.2 µM (n = 6) in controls (biological replicates, mean ± s.d., P = 0.0001)). Unlike nonresistant clones, resistant clones maintained normal mitochondrial and nucleolar morphology during mitotane treatment. Resistant clones largely shared structural and single nucleotide variants, suggesting a common cell of origin. Resistance depended, in part, on extracellular lipoproteins and was associated with alterations in intracellular lipid homeostasis, including levels of free cholesterol, as well as decreased steroid production. By gene expression analysis, resistant cells showed profound alterations in pathways including steroid metabolism and transport, apoptosis, cell growth and Wnt signaling. These studies establish an in vitro model of mitotane resistance in ACC and point to underlying molecular mechanisms. They may enable future studies to overcome resistance in vitro and improve ACC treatment in vivo.

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“…It has been shown that mitotane has a low oral bioavailability (F) of 35-40% (11) and a high volume of distribution, which is likely due to its lipophilic nature and extensive accumulation in adipose tissue (12). The majority of mitotane has been found to be bound to lipoprotein particles in circulation with pharmacological activity limited to the unbound fraction (13,14,15).…”

Section: Introductionmentioning

confidence: 99%

Enzyme autoinduction by mitotane supported by population pharmacokinetic modeling in a large cohort of adrenocortical carcinoma patients

Arshad

Taubert

Kurlbaum

et al. 2018

European Journal of Endocrinology

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Objective Mitotane is used for the treatment of adrenocortical carcinoma. High oral daily doses of typically 1–6 g are required to attain therapeutic concentrations. The drug has a narrow therapeutic index and patient management is difficult because of a high volume of distribution, very long elimination half-life and drug interaction through induction of metabolizing enzymes. The present evaluation aimed at the development of a population pharmacokinetic model of mitotane to facilitate therapeutic drug monitoring (TDM). Methods Appropriate dosing information, plasma concentrations (1137 data points) and covariates were available from TDM of 76 adrenocortical carcinoma patients treated with mitotane. Using nonlinear mixed-effects modeling, a simple structural model was first developed, with subsequent introduction of metabolic autoinduction. Covariate data were analyzed to improve overall model predictability. Simulations were performed to assess the attainment of therapeutic concentrations with clinical dosing schedules. Results A one-compartment pharmacokinetic model with first order absorption was found suitable to describe the data, with an estimated central volume of distribution of 6086 L related to a high interindividual variability of 81.5%. Increase in clearance of mitotane during treatment could be modeled by a linear enzyme autoinduction process. BMI was found to have an influence upon disposition kinetics of mitotane. Model simulations favor a high-dose regimen to rapidly attain therapeutic concentrations, with the first TDM suggested on day 16 of treatment to avoid systemic toxicity. Conclusion The proposed model describes mitotane pharmacokinetics and can be used to facilitate therapy by predicting plasma concentrations.

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Association of mitotane with chylomicrons and serum lipoproteins: practical implications for treatment of adrenocortical carcinoma

Cited by 23 publications

References 45 publications

A Micellar Mitotane Formulation with High Drug‐Loading and Solubility: Physico‐Chemical Characterization and Cytotoxicity Studies in 2D and 3D In Vitro Tumor Models

A Micellar Mitotane Formulation with High Drug‐Loading and Solubility: Physico‐Chemical Characterization and Cytotoxicity Studies in 2D and 3D In Vitro Tumor Models

Generation and characterization of a mitotane-resistant adrenocortical cell line

Enzyme autoinduction by mitotane supported by population pharmacokinetic modeling in a large cohort of adrenocortical carcinoma patients

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