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...
Saved in:
| Main Authors: | , , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
2015
|
| 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
|
| Author Notes: | Dirk Theile, Walter Emil Haefeli, Johanna Weiss |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1702919617 | ||
| 003 | DE-627 | ||
| 005 | 20240406193221.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 200630r20152014xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1007/s12020-014-0517-2 |2 doi | |
| 035 | |a (DE-627)1702919617 | ||
| 035 | |a (DE-599)KXP1702919617 | ||
| 035 | |a (OCoLC)1341342058 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 33 |2 sdnb | ||
| 100 | 1 | |a Theile, Dirk |e VerfasserIn |0 (DE-588)1019114428 |0 (DE-627)684195658 |0 (DE-576)356996360 |4 aut | |
| 245 | 1 | 0 | |a Effects of adrenolytic mitotane on drug elimination pathways assessed in vitro |c Dirk Theile, Walter Emil Haefeli, Johanna Weiss |
| 264 | 1 | |c 2015 | |
| 300 | |a 12 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Published online: 27 December 2014 | ||
| 500 | |a Gesehen am 30.06.2020 | ||
| 520 | |a 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. | ||
| 534 | |c 2014 | ||
| 700 | 1 | |a Haefeli, Walter E. |d 1958- |e VerfasserIn |0 (DE-588)124572359 |0 (DE-627)656806141 |0 (DE-576)340514221 |4 aut | |
| 700 | 1 | |a Weiß, Johanna |e VerfasserIn |0 (DE-588)1050230906 |0 (DE-627)783666322 |0 (DE-576)404441114 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Endocrine |d [Erscheinungsort nicht ermittelbar] : Springer, 1995 |g 49(2015), 3, Seite 842-853 |h Online-Ressource |w (DE-627)343970171 |w (DE-600)2074043-8 |w (DE-576)273833561 |x 1559-0100 |7 nnas |a Effects of adrenolytic mitotane on drug elimination pathways assessed in vitro |
| 773 | 1 | 8 | |g volume:49 |g year:2015 |g number:3 |g pages:842-853 |g extent:12 |a Effects of adrenolytic mitotane on drug elimination pathways assessed in vitro |
| 856 | 4 | 0 | |u https://doi.org/10.1007/s12020-014-0517-2 |x Verlag |x Resolving-System |z lizenzpflichtig |3 Volltext |
| 951 | |a AR | ||
| 992 | |a 20200630 | ||
| 993 | |a Article | ||
| 994 | |a 2015 | ||
| 998 | |g 1050230906 |a Weiß, Johanna |m 1050230906:Weiß, Johanna |d 910000 |d 910100 |e 910000PW1050230906 |e 910100PW1050230906 |k 0/910000/ |k 1/910000/910100/ |p 3 |y j | ||
| 998 | |g 124572359 |a Haefeli, Walter E. |m 124572359:Haefeli, Walter E. |d 910000 |d 910100 |e 910000PH124572359 |e 910100PH124572359 |k 0/910000/ |k 1/910000/910100/ |p 2 | ||
| 998 | |g 1019114428 |a Theile, Dirk |m 1019114428:Theile, Dirk |d 910000 |d 910100 |e 910000PT1019114428 |e 910100PT1019114428 |k 0/910000/ |k 1/910000/910100/ |p 1 |x j | ||
| 999 | |a KXP-PPN1702919617 |e 3692345836 | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"physDesc":[{"extent":"12 S."}],"note":["Published online: 27 December 2014","Gesehen am 30.06.2020"],"person":[{"role":"aut","given":"Dirk","family":"Theile","display":"Theile, Dirk"},{"role":"aut","given":"Walter E.","display":"Haefeli, Walter E.","family":"Haefeli"},{"role":"aut","given":"Johanna","family":"Weiß","display":"Weiß, Johanna"}],"title":[{"title":"Effects of adrenolytic mitotane on drug elimination pathways assessed in vitro","title_sort":"Effects of adrenolytic mitotane on drug elimination pathways assessed in vitro"}],"id":{"doi":["10.1007/s12020-014-0517-2"],"eki":["1702919617"]},"origin":[{"dateIssuedKey":"2015","dateIssuedDisp":"2015"}],"type":{"media":"Online-Ressource","bibl":"article-journal"},"name":{"displayForm":["Dirk Theile, Walter Emil Haefeli, Johanna Weiss"]},"relHost":[{"pubHistory":["Nachgewiesen 3.1995 -"],"type":{"bibl":"periodical","media":"Online-Ressource"},"language":["eng"],"part":{"year":"2015","volume":"49","issue":"3","pages":"842-853","text":"49(2015), 3, Seite 842-853","extent":"12"},"recId":"343970171","disp":"Effects of adrenolytic mitotane on drug elimination pathways assessed in vitroEndocrine","physDesc":[{"extent":"Online-Ressource"}],"note":["Gesehen am 11.06.2018","Fortsetzung der Druck-Ausgabe"],"id":{"zdb":["2074043-8"],"eki":["343970171"],"issn":["1559-0100"]},"title":[{"title":"Endocrine","title_sort":"Endocrine"}],"origin":[{"dateIssuedKey":"1995","dateIssuedDisp":"1995-","publisher":"Springer ; Humana Press","publisherPlace":"[Erscheinungsort nicht ermittelbar] ; Totowa, NJ"}]}],"language":["eng"],"recId":"1702919617"} | ||
| SRT | |a THEILEDIRKEFFECTSOFA2015 | ||