Bovine adrenal cortex transformations of mitotane [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane; o,p′-DDD] and its p,p′- and m,p′-isomers

Cai, Wei; Benitez, Richardo; Counsell, Raymond E.; Djanegara, Tanya; Schteingart, D.E.; Sinsheimer, Joseph E.; Wotring, Linda L.

doi:10.1016/0006-2952(95)00028-x

Cited by 30 publications

(14 citation statements)

References 21 publications

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“…The human blood data show that DDA is the most represented and that all three compounds are more concentrated in plasma than in red cells. DDA is a metabolite ready for elimination but also the end product of a process in which highly reactant intermediate acyl-chloride is formed as has been suggested in bovine studies [11]. Plasma and red cell DDD are correlated and hence red cell DDD concentrations can be deduced from the plasma data and the plasma DDE concentration can be deduced from the DDD concentration.…”

Section: Animalsmentioning

confidence: 97%

“…DDD's exact antitumour molecular mechanism is unknown and it is still unclear whether it is induced by DDD itself or one of its metabolites such as DDE or DDA following ␣-and ␤-hydroxylation, respectively ( Fig. 1) [11]. Monitoring plasma DDD and its metabolite levels is thus required to combine good therapeutic efficacy with acceptable toxicity.…”

Section: Introductionmentioning

confidence: 98%

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A new simple HPLC method for measuring mitotane and its two principal metabolites

Francia

Pirro

Zappia³

et al. 2006

Journal of Chromatography B

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Section: Animalsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

A new simple HPLC method for measuring mitotane and its two principal metabolites

Francia

Pirro

Zappia³

et al. 2006

Journal of Chromatography B

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“…Redistribution of mitotane between fatty tissues and plasma might cause fluctuation in mitotane levels. This mechanism is mainly influenced by transport in both directions, binding of mitotane to plasma lipoproteins, and metabolization into 2,4-dichlorodiphenyl acetic acid (17,18). Probably, mitotane clearance has a minor impact on the plasma level.…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

Short-term variation in plasma mitotane levels confirms the importance of trough level monitoring

Kerkhofs

Derijks

Ettaieb

et al. 2014

European Journal of Endocrinology

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Objective: Mitotane is the drug of choice in patients with adrenocortical carcinoma. The anti-neoplastic effect is correlated with mitotane plasma levels, which render it crucial to reach and maintain the concentration above 14 mg/l. However, mitotane pharmacokinetics is poorly understood. The aim of this study was to investigate the variation in plasma mitotane levels during the day and the influence of a single morning dose. Design: A prospective case-control study was conducted to investigate the variation in plasma mitotane levels. Methods: Patients who had been treated for at least 24 weeks and had reached the therapeutic plasma level (14 mg/l) at least once were eligible. In the first group, mitotane levels were determined hourly for the duration of 8 h after administration of a single morning dose. In the second group, mitotane levels were assessed similarly without administration of a morning dose. Results: Ten patients were included in this study, and three patients participated in both groups. Median plasma level at baseline was 16.2 mg/l (range 11.3-23.3 mg/l) in the first group (nZ7) and 17.0 mg/l (13.7-23.8) in the second group (nZ6). Plasma levels displayed a median increase compared with baseline of 24% (range 6-42%) at tZ4 after morning dose and a change of 13% (range K14 to 33%) at tZ4 without morning dose (PZ0.02). Conclusion: A substantial increase in mitotane plasma levels was observed in steady-state patients within a period of 8 h after morning dosing. Without morning dose, mitotane curves showed a variable profile throughout the day. This implies that random sampling could yield incidentally high levels. For this reason, we recommend early-morning trough sampling as standard management in monitoring mitotane treatment.

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“…Mitotane is a steroidogenesis inhibitor at diff erent enzymatic steps, which concentrates in the adrenal glands and is thought to provoke mitochondrial degeneration and destruction of the adrenal cortex [ 11 ] . However, the precise mechanisms of action remain still unknown.…”

Section: Hair Cortisol Measurement In Mitotane-treated Adrenocorticalmentioning

confidence: 99%

Hair Cortisol Measurement in Mitotane-Treated Adrenocortical Cancer Patients

2014

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The only approved drug for the treatment of adrenocortical cancer (ACC) is mitotane. Mitotane is adrenolytic and therefore, hydrocortisone replacement therapy is necessary. Since mitotane increases cortisol binding globulin (CBG) and induces CYP3A4 activity, high doses of hydrocortisone are thought to be required. Evaluation of hydrocortisone therapy in mitotane-treated patients has been difficult since there is no good marker to evaluate hydrocortisone therapy. Measurement of cortisol in scalp hair is a novel method that offers the opportunity to measure long-term cortisol levels. Our aim was to evaluate whether hair cortisol measurements could be useful in evaluating recent hydrocortisone treatment in mitotane-treated ACC patients. Hair cortisol levels were measured in 15 mitotane-treated ACC patients on hydrocortisone substitution and 96 healthy individuals. Cortisol levels were measured in 3 cm hair segments, corresponding to a period of 3 months. Hair cortisol levels were higher in ACC patients compared to healthy individuals (p<0.0001). Seven ACC patients (47%) had hair cortisol levels above the reference range. None of the patients had hair cortisol levels below normal. In contrast to hydrocortisone doses (β=0.03, p=0.93), hair cortisol levels were associated with BMI (β=0.53, p=0.042). There was no correlation between hair cortisol levels and hydrocortisone doses (β=0.41, p=0.13). Almost half of the ACC patients had high hair cortisol levels, suggesting long-term over-substitution of hydrocortisone in some of the patients, whereas none of the patients was under-substituted. Hair cortisol measurements might be useful in long-term monitoring hydrocortisone treatment in mitotane-treated ACC patients.

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Bovine adrenal cortex transformations of mitotane [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane; o,p′-DDD] and its p,p′- and m,p′-isomers

Cited by 30 publications

References 21 publications

A new simple HPLC method for measuring mitotane and its two principal metabolites

A new simple HPLC method for measuring mitotane and its two principal metabolites

Short-term variation in plasma mitotane levels confirms the importance of trough level monitoring

Hair Cortisol Measurement in Mitotane-Treated Adrenocortical Cancer Patients

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