Effects of adrenolytic mitotane on drug elimination pathways assessed in vitro
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) part...
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| Main Authors: | , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2015
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| In: |
Endocrine
Year: 2014, Volume: 49, Issue: 3, Pages: 842-853 |
| ISSN: | 1559-0100 |
| DOI: | 10.1007/s12020-014-0517-2 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1007/s12020-014-0517-2
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| Author Notes: | Dirk Theile, Walter Emil Haefeli, Johanna Weiss |
| Summary: | 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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| Item Description: | Published online: 27 December 2014 Gesehen am 30.06.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1559-0100 |
| DOI: | 10.1007/s12020-014-0517-2 |