insecticide dichlorodiphenyldichloroethane, has been widely used in ACC therapy due to its adrenolytic properties ( 4 , 5 ). A retrospective study demonstrated an association of adjuvant mitotane with prolonged recurrence-free survival after radical resection
Eric Seidel, Gudrun Walenda, Clemens Messerschmidt, Benedikt Obermayer, Mirko Peitzsch, Paal Wallace, Rohini Bahethi, Taekyeong Yoo, Murim Choi, Petra Schrade, Sebastian Bachmann, Gerhard Liebisch, Graeme Eisenhofer, Dieter Beule and Ute I Scholl
L Ghataore, I Chakraborti, S J Aylwin, K-M Schulte, D Dworakowska, P Coskeran and N F Taylor
Mitotane (o,p'-DDD), an oral adrenolytic agent for treatment of advanced adrenocortical carcinoma (ACC), is reported to inhibit cortisol biosynthesis in vitro and enhance production from exogenous cortisol of urinary 6β-hydroxycortisol and unidentified polar unconjugated metabolites. We examined urinary steroid profiles by gas chromatography–mass spectrometry of patients with histologically confirmed ACC following surgery, receiving a) hydrocortisone alone (three males and three females) and b) mitotane and hydrocortisone (six males and 11 females). Samples were collected after plasma mitotane had reached the therapeutic range of 14–20 mg/l. Increased excretion of polar unconjugated steroids during mitotane treatment was confirmed, with 6β-hydroxycortisol and 6β-hydroxy-20-dihydrocortisols predominating. The proportion of additionally hydroxylated metabolites was <2% in untreated controls and 52, 35–52% (mean, range) in the mitotane plus hydrocortisone group. Ratios of 5α-/5β- and 20β-/20α-metabolites of administered cortisol were decreased 50-, 15-fold, and 14-, 8-fold respectively (males, females – mean values) but with no change in metabolite ratios that reflect oxidoreduction at C11 or C20. Patterns of decrease in 5α- relative to 5β-reduced metabolites were similar to those of patients with 5α-reductase 2 deficiency or on treatment with the 5α-reductase 2 inhibitor finasteride but different from those of patients on dutasteride, indicating specific inhibition of 5α-reductase 2. We conclude that mitotane causes consistent changes in cortisol catabolism, most of which have not been previously recognised. These need not interfere with early detection of ACC recurrence. Induction of 6β-hydroxylation offers an explanation for a reported decrease in cortisol bioavailability. Mitotane also has potential as a unique steroid metabolic probe for 20β-reduction.
Emmanuelle Motte, Anya Rothenbuhler, Stephan Gaillard, Najiba Lahlou, Cécile Teinturier, Régis Coutant and Agnès Linglart
, 15 , 16 ), prompting physicians to use alternative therapies such as pituitary radiotherapy or adrenolytic agents. O,p’-dichlorodiphenyldichloroethane (mitotane, Lysodren 500 mg; HRA Pharma, Paris, France) is an adrenolytic drug with a direct
Anne Jouinot, Bernard Royer, Etienne Chatelut, Sotheara Moeung, Guillaume Assié, Audrey Thomas-Schoemann, Jérôme Bertherat, François Goldwasser and Benoit Blanchet
Clinical Pharmacology 1998 54 677 – 683 . ( https://doi.org/10.1007/s002280050534 ) 6 Theile D Haefeli WE Weiss J. Effects of adrenolytic mitotane on drug elimination pathways assessed in vitro . Endocrine 2015 49 842 – 853 . ( https