A simple HPLC method for plasma level monitoring of mitotane and its two main metabolites in adrenocortical cancer patients

Garg, Mukesh; Sakoff, Jennette A.; Ackland, Stephen P.

doi:10.1016/j.jchromb.2011.06.001

Cited by 15 publications

(24 citation statements)

References 24 publications

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“…Knowledge about the effect of mitotane on anemia is scarce [7,8]. It must be kept in mind, that the drug is used in malignancy [1,2,3], a disorder causing anemia [53]. Thus, during mitotane treatment the eryptotic effects of mitotane may be outweighed by the effects of decreasing tumor mass.…”

Section: Discussionmentioning

confidence: 99%

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Stimulation of Erythrocyte Cell Membrane Scrambling by Mitotane

Jacobi¹,

Lang²,

Bissinger³

et al. 2014

Cell Physiol Biochem

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Background: Mitotane (1,1-dichloro-2-[o-chlorophenyl]-2-[p-chlorophenyl]ethane), a cytostatic drug used for the treatment of adrenocortical carcinomas, is effective by triggering tumor cell apoptosis. In analogy to apoptosis of nucleated cells, eryptosis is the suicidal death of erythrocytes, which is typically paralleled by cell shrinkage and breakdown of cell membrane phosphatidylserine asymmetry with subsequent phosphatidylserine exposure at the erythrocyte surface. Eryptosis may be triggered by increase of cytosolic Ca²⁺ concentration ([Ca²⁺]_i). The present study tested, whether treatment of human erythrocytes with mitotane is followed by eryptosis. Methods: [Ca²⁺]_i was estimated from Fluo3 fluorescence, cell volume from forward scatter, phosphatidylserine exposure from annexin V binding, and hemolysis from hemoglobin release. Results: Exposure to mitotane (≥ 5 µg/ml ≈ 16 µM) significantly increased [Ca²⁺]_i, increased annexin V binding and triggered hemolysis, but did not significantly modify forward scatter. The effect on annexin V binding was significantly blunted in the absence of extracellular Ca²⁺. Within 30 min Ca²⁺ ionophore ionomycin (1 µM) decreased forward scatter, an effect virtually abolished in the presence of mitotane (15 µg/ml). Conclusions: Mitotane increases [Ca²⁺]_i with subsequent phosphatidylserine translocation. By the same token mitotane inhibits Ca²⁺ induced cell shrinkage.

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Section: Discussionmentioning

confidence: 99%

“…Mitotane (1,1-dichloro-2-[o-chlorophenyl]-2-[p-chlorophenyl]ethane) is the drug of choice for non-resectable and metastatic adrenocortical carcinoma, a rare malignancy with a 5-year survival of less than 50% [1,2,3]. The substance is effective by triggering apoptosis of tumor cells [4,5,6], an effect attributed to caspase activation [4].…”

Section: Introductionmentioning

confidence: 99%

Stimulation of Erythrocyte Cell Membrane Scrambling by Mitotane

Jacobi¹,

Lang²,

Bissinger³

et al. 2014

Cell Physiol Biochem

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“…In fact, mitotane metabolism is being studied for almost four decades to better understand its pharmacokinetics and pharmacodynamics and so, its molecular activity, which would help in carrying out the treatment [61][62][63][64][65][66][67][68][69][70]. Several approaches, using chromatography and/or spectrometry, have been developed to quantitatively determine mitotane and its metabolites in body fluids (e.g.…”

Section: Biological Effects and Pharmacological Propertiesmentioning

confidence: 99%

“…Several approaches, using chromatography and/or spectrometry, have been developed to quantitatively determine mitotane and its metabolites in body fluids (e.g. serum, plasma, and urine) as well as in feces, and associate them with clinical outcomes [61,[66][67][68][69][70]. Among the major mitotane metabo- [61], and o,p'-DDA (1,1-(o,p'-dichlorodiphenyl) acetic acid) [62] which has been identified through a proposed route involving the adrenal mitochondrial cytochrome P450-catalyzed hydroxylation of mitotane at the -carbon [63,64].…”

Section: Biological Effects and Pharmacological Propertiesmentioning

confidence: 99%

“…Interestingly, it was shown using GC-MS/Selected Ion Monitoring (SIM) that o,p'-DDA is present in the plasma at a concentration about 10 times higher than the levels of o,p'-DDD (mitotane) and o,p'-DDE [67]. This finding was later confirmed by other approaches using HPLC separation [61,68]. The clinical significance of such high plasmatic o,p'-DDA levels is not established yet.…”

Section: Biological Effects and Pharmacological Propertiesmentioning

confidence: 99%

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Development of Mitotane Lipid Nanocarriers and Enantiomers: Two-in-One Solution to Efficiently Treat Adreno-Cortical Carcinoma

Menaa¹,

Menaa²

2012

CMC

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Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with a poor prognosis. Treatment options for advanced ACC are limited. Indeed, radical tumor resection can lead to local or metastatic recurrence, and mitotane (Lysodren(®)), the only recognized adrenolytic drug, offers modest response rates, notably due to some of its physico-chemical and pharmacological properties (i.e. hydrophobicity, low bioavailability). Meantime, high cumulative doses of Lysodren(®) usually cause systemic toxicities. To reduce adverse health effects, the search of safe and efficient mitotane nano-formulations as well as the full characterization and testing of its enantiomers can represent valuable therapeutic options. Interestingly, recent investigations showed that solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) could considerably improve the efficacy of mitotane (i.e. enhanced solubility and bioavailability, progressive release of the loaded drug into blood and targeted tissues) as well as its safety (i.e. lower toxicity, higher biocompatibility). These two nano-carriers for mitotane delivery and targeting are of particular interest over other polymeric particles (i.e. low-cost, efficient and simple scaling to an industrial production level following green methods). Besides, emerging studies suggested that the S-(-)- mitotane is more potent than the R-(+)-mitotane for ACC treatment. Therefore, the production of pure and active S-(-)-mitotane might offer synergic or additive benefits for ACC patients when combined to solid lipid-based nanocarriers. In this review, we first provide an updated overview of the ACC disease before emphasizing on the promising mitotane drug nano-systems, as well as on the separation, purification and production of single mitotane enantiomer using state-of-art chromatographic-based methods.

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Simultaneous analysis of mitotane and its main metabolites in human blood and urine samples by SPE‐HPLC technique

Mornar

Sertić

Turk

et al. 2012

Biomedical Chromatography

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Adrenocortical carcinoma (ACC) is a rare malignancy with an incompletely understood pathogenesis and a poor prognosis. The adrenalytic activity of mitotane has made it the most important single drug in the treatment of ACC. Unfortunately, the exact mechanism of mitotane action is still unknown. It is believed that mitotane belongs to the class of drugs that require metabolic transformation by cytochrome P450 for therapeutic action; therefore determination of plasma levels of not only mitotane but also its metabolites would help in carrying out the treatment. The objective of this work was to develop and validate an SPE-HPLC method for simultaneous determination of mitotane and its metabolites in different biological fluids. The sample preparation consisted of a solid-phase extraction on a Discovery DSC(18) cartridge, while analysis of extracts was performed on a Symmetry C(18) column. The usefulness of the proposed method was confirmed by analysis of plasma, red cell and urine samples from patient chronically treated with 1.5 g of mitotane. The patient involved in this study had a high plasma concentration of mitotane and none of the investigated metabolites were found. In order to investigate whether the polymorphism of CYP2C9 and CYP2C19 enzymes could be related to the metabolism of mitotane, RT-PCR analysis was performed.

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A simple HPLC method for plasma level monitoring of mitotane and its two main metabolites in adrenocortical cancer patients

Cited by 15 publications

References 24 publications

Stimulation of Erythrocyte Cell Membrane Scrambling by Mitotane

Stimulation of Erythrocyte Cell Membrane Scrambling by Mitotane

Development of Mitotane Lipid Nanocarriers and Enantiomers: Two-in-One Solution to Efficiently Treat Adreno-Cortical Carcinoma

Simultaneous analysis of mitotane and its main metabolites in human blood and urine samples by SPE‐HPLC technique

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