HEPATIC MICROSOMAL ENZYME INDUCTION AND ADRENAL CRISIS DUE TO o,p’DDD THERAPY FOR METASTATIC ADRENOCORTICAL CARCINOMA

Hague, R. V.; May, William N.; Cullen, D. R.

doi:10.1111/j.1365-2265.1989.tb00453.x

Cited by 43 publications

(23 citation statements)

References 30 publications

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“…In accordance, a case report described an interaction between mitotane and the anticoagulant warfarin which resulted in increased warfarin requirements, suggesting induction of metabolizing enzymes by mitotane (9). Additionally, a substantial increase in steroid requirement was described in two patients, but observed generally in clinical practice, on mitotane therapy which was explained by hepatic microsomal enzyme induction (10). Also an increase in bleeding time due to mitotane treatment was noticeably caused by defective platelet function (11).…”

Section: Introductionsupporting

confidence: 50%

Mitotane has a strong and a durable inducing effect on CYP3A4 activity

Erp

Guchelaar

Ploeger³

et al. 2011

European Journal of Endocrinology

103

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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) mg!h/l respectively PZ0.001) 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) mg!h/l, PZ0.008). Sunitinib exposure was decreased in the two patients who were co-treated with mitotane (267 and 268 mg!h/l versus 1344 (1079-1609) (mean (95% CI)) mg!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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Section: Introductionsupporting

confidence: 50%

Mitotane has a strong and a durable inducing effect on CYP3A4 activity

Erp

Guchelaar

Ploeger³

et al. 2011

European Journal of Endocrinology

103

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“…Eleven patients had plasma ACTH (2AE73 ± 0AE71 pmol/l, range: 1AE11-8AE22) and mitotane levels (16AE6 ± 0AE52 mg/l, range: [14][15][16][17][18][19][20] in the target range, and they also had FC (62AE10 ± 19AE91, P = 0AE24) Total studied samples r-= 0·78, P < 0·001 r-= 0·80, P < 0·001 r-= 0·70, P < 0·03 r-= 0·90, P < 0·001 r-= 0·58, P < 0·008 r-= 0·97, P < 0·001 r-= 0·58, P < 0·004 r-= 0·97, P < 0·001 The correlations between free cortisol levels and free cortisol index in the total samples studied, and in samples from patients of the different subgroups studied.…”

Section: Resultsmentioning

confidence: 99%

“…10,11 Therapeutic drug level monitoring is routinely performed in only few centres, but may be offered as service by the pharmaceutical company provider. [10][11][12][13][14][15] As mitotane affects all adrenocortical zones, glucocorticoid and mineralocorticoid replacement therapy have to be considered. Measurement of plasma adrenocorticotrophin (ACTH) or urinaryfree cortisol (UFC) has been suggested to evaluate adrenal steroid secretion and adjust the dose of cortisol replacement to assure adequate adrenal replacement and avoid adrenal insufficiency in this situation.…”

Section: Introductionmentioning

confidence: 99%

“…Cortisol circulates in blood largely bound to CBG and albumin, 17 with the much smaller amount of unbound hormone responsible for its metabolic effects. 15,18,19 It is assumed that the biologically active level of cortisol to which tissues are exposed is free cortisol (FC). Routinely available assays of adrenal function measure serum TC, but not the biologically active FC; it is usually considered that TC broadly correlates with the biologically-free fraction.…”

Section: Introductionmentioning

confidence: 99%

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Assessment of serum‐free cortisol levels in patients with adrenocortical carcinoma treated with mitotane: a pilot study

Alexandraki

Kaltsas

Roux

et al. 2010

Clinical Endocrinology

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SummaryObjective Mitotane treatment in adrenocortical carcinoma (ACC) results in unreliable measurement of serum total cortisol (TC) levels because of an elevation in corticosteroid-binding globulin (CBG). Design The use of a newly-developed serum-free cortisol (FC) assay was assessed to investigate the characteristics of a more valid measure of cortisol status. Patients Sixty-two serum samples from patients with ACC treated with mitotane were studied. Different subgroups were studied according to mitotane levels (<14, 14-20 and >20 mg/dl), hydrocortisone replacement treatment, presence of Cushing's syndrome (CS) and adrenocorticotrophin (ACTH) levels. Measurements Serum FC was measured using a newlydeveloped assay, TC, CBG and plasma ACTH using conventional laboratory kits; TC-to-CBG (Free cortisol index, FCI, nmol/mg) and TC-to-FC (TFR) ratios were calculated. Results CBG levels were elevated and positively correlated to mitotane levels. FC was positively related to TC and FCI in nearly all subgroups studied. Plasma ACTH was negatively related to parameters of cortisol levels in the total samples studied. In the 'target' subgroup with normal ACTH levels and mitotane levels 14-20 mg/dl, no correlation of plasma ACTH with any parameter studied was seen, and FC suggested over-replacement with hydrocortisone treatment in the subgroup with CS. Conclusions FC measurement may offer additional information in the follow-up of patients on mitotane, especially when there is a history of CS which invalidates the use of acute changes in plasma ACTH as a parameter of hydrocortisone replacement. These preliminary data suggest that it may prove useful as a biochemical marker when TC or FCI are invalidated by mitotane treatment or plasma ACTH is suppressed by hypercortisolaemia. Larger studies are needed to substantiate the clinical utility of FC measurement in specific groups of patients.

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“…Mitotane increases the metabolic clearance of exogenously administered steroid and the replacement dose of steroid is increased by about a third (28). In order to minimise side effects mitotane dose should be gradually titrated up, taken with meals or at bedtime with food.…”

Section: Pharmacological Management Of Csmentioning

confidence: 99%

Pharmacological management of Cushing's syndrome: an update

Dang

Trainer

2007

Arq Bras Endocrinol Metab

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The treatment of choice for Cushing's syndrome remains surgical. The role for medical therapy is twofold. Firstly it is used to control hypercortisolaemia prior to surgery to optimize patient's preoperative state and secondly, it is used where surgery has failed and radiotherapy has not taken effect. The main drugs used inhibit steroidogenesis and include metyrapone, ketoconazole, and mitotane. RESUMOManejo Farmacológico da Síndrome de Cushing: Uma Atualização. O tratamento de escolha para a síndrome de Cushing ainda é a cirurgia. O papel da terapia medicamentosa é duplo: ele é usado para controlar o hipercortisolismo antes da cirurgia e otimizar o estado pré-operatório do paciente e, adicionalmente, quando ocorre falha cirúrgica e a radioterapia ainda não se mostrou efetiva. Os principais medicamentos são empregados para inibir a esteroidogênese e incluem: metirapona, cetoconazol e mitotano. Medicamentos visando o eixo hipotálamo-hipofisário têm sido investigados, mas seu papel na prática clínica permanece limitado, embora o agonista PPAR-γ e análogo de somatostatina, som-230 (pasireotídeo), requeira estudos adicionais. A única droga que age perifericamente no receptor glicocorticóide é a mifepristona (RU486). O manejo da síndrome de Cushing deve envolver uma combinação terapêutica atuando em diferentes vias da hipercortisolemia, mas o monitoramento dessa terapia ainda permanece um desafio. (Arq Bras Endocrinol Metab

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HEPATIC MICROSOMAL ENZYME INDUCTION AND ADRENAL CRISIS DUE TO o,p’DDD THERAPY FOR METASTATIC ADRENOCORTICAL CARCINOMA

Cited by 43 publications

References 30 publications

Mitotane has a strong and a durable inducing effect on CYP3A4 activity

Mitotane has a strong and a durable inducing effect on CYP3A4 activity

Assessment of serum‐free cortisol levels in patients with adrenocortical carcinoma treated with mitotane: a pilot study

Pharmacological management of Cushing's syndrome: an update

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