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Effects of adrenolytic mitotane on drug elimination pathways assessed in vitro

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Abstract

Mitotane (1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane, o,p′-DDD) represents one of the most active drugs for the treatment of adrenocortical carcinoma. Its metabolites 1,1-(o,p′-dichlorodiphenyl) acetic acid (=o,p′-DDA) and 1,1-(o,p′-dichlorodiphenyl)-2,2 dichloroethene (=o,p′-DDE) partly contribute to its pharmacological effects. Because mitotane has a narrow therapeutic index and causes pharmacokinetic drug–drug interactions, knowledge about these compounds’ effects on drug metabolizing and transporting proteins is crucial. Using quantitative real-time polymerase chain reaction, our study confirmed the strong inducing effects of o,p′-DDD on mRNA expression of cytochrome P450 3A4 (CYP3A4, 30-fold) and demonstrated that other enzymes and transporters are also induced (e.g., CYP1A2, 8.4-fold; ABCG2 (encoding breast resistance cancer protein, BCRP), 4.2-fold; ABCB1 (encoding P-glycoprotein, P-gp) 3.4-fold). P-gp induction was confirmed at the protein level. o,p′-DDE revealed a similar induction profile, however, with less potency and o,p′-DDA had only minor effects. Reporter gene assays clearly confirmed o,p′-DDD to be a PXR activator and for the first time demonstrated that o,p′-DDE and o,p′-DDA also activate PXR albeit with lower potency. Using isolated, recombinant CYP enzymes, o,p′-DDD and o,p′-DDE were shown to strongly inhibit CYP2C19 (IC50 = 0.05 and 0.09 µM). o,p′-DDA exhibited only minor inhibitory effects. In addition, o,p′-DDD, o,p′-DDE, and o,p′-DDA are demonstrated to be neither substrates nor inhibitors of BCRP or P-gp function. In summary, o,p′-DDD and o,p′-DDE might be potential perpetrators in pharmacokinetic drug–drug interactions through induction of drug-metabolizing enzymes or drug transporters and by potent inhibition of CYP2C19. In tumors over-expressing BCRP or P-gp, o,p′-DDD and its metabolites should retain their efficacy due to a lack of substrate characteristics.

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Acknowledgments

We would like to thank Dr. Johannes Pöschl for providing access to the flow cytometer. We also thank Corina Mueller, Jutta Kocher, and Stephanie Rosenzweig for excellent technical assistance and Dr. Andreas Meid for his help with statistics.

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The authors declare that they have no conflict of interest.

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  1. Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    Dirk Theile, Walter Emil Haefeli & Johanna Weiss

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Theile, D., Haefeli, W.E. & Weiss, J. Effects of adrenolytic mitotane on drug elimination pathways assessed in vitro. Endocrine 49, 842–853 (2015). https://doi.org/10.1007/s12020-014-0517-2

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