{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T22:56:43Z","timestamp":1791845803245,"version":"4.3.4"},"reference-count":100,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2021,2,2]],"date-time":"2021-02-02T00:00:00Z","timestamp":1612224000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["001"],"award-info":[{"award-number":["001"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004612","name":"Funda\u00e7\u00e3o Arauc\u00e1ria","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004612","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:p>Mitotane is the only adrenolytic drug approved by the Food and Drug Administration for treating adrenocortical carcinoma (ACC). This drug has cytotoxic effects on tumour tissues; it induces cell death and antisecretory effects on adrenal cells by inhibiting the synthesis of adrenocortical steroids, which are involved in the pathogenesis of ACC. However, high doses of mitotane are usually necessary to reach the therapeutic plasma concentration, which may result in several adverse effects. This suggests that important pharmacological processes, such as first pass metabolism, tissue accumulation and extensive time for drug elimination, are associated with mitotane administration. Few studies have reported the pharmacological aspects and therapeutic effects of mitotane. Therefore, the aim of this review was to summarize the chemistry, pharmacokinetics and pharmacodynamics, and therapeutic and toxic effects of mitotane. This review also discusses new perspectives of mitotane formulation that are currently under investigation. Understanding the pharmacological profile of mitotane can improve the monitoring and efficacy of this drug in ACC treatment and can provide useful information for the development of new drugs with specific action against ACC with fewer adverse effects.<\/jats:p>","DOI":"10.1111\/bcp.14721","type":"journal-article","created":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T06:56:43Z","timestamp":1609397803000},"page":"2698-2710","source":"Crossref","is-referenced-by-count":60,"title":["Pharmacological profile and effects of mitotane in adrenocortical carcinoma"],"prefix":"10.1111","volume":"87","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6594-3542","authenticated-orcid":false,"given":"Claudia Rita","family":"Corso","sequence":"first","affiliation":[{"name":"Instituto de Pesquisa Pel\u00e9 Pequeno Pr\u00edncipe  Curitiba Brazil"},{"name":"Faculdades Pequeno Pr\u00edncipe  Curitiba Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3977-687X","authenticated-orcid":false,"given":"Alexandra","family":"Acco","sequence":"additional","affiliation":[{"name":"Pharmacology Department Federal University of Paran\u00e1  Curitiba Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2910-2679","authenticated-orcid":false,"given":"Camila","family":"Bach","sequence":"additional","affiliation":[{"name":"Instituto de Pesquisa Pel\u00e9 Pequeno Pr\u00edncipe  Curitiba Brazil"},{"name":"Faculdades Pequeno Pr\u00edncipe  Curitiba Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7262-3766","authenticated-orcid":false,"given":"Sandro Jos\u00e9 Ribeiro","family":"Bonatto","sequence":"additional","affiliation":[{"name":"Instituto de Pesquisa Pel\u00e9 Pequeno Pr\u00edncipe  Curitiba Brazil"},{"name":"Faculdades Pequeno Pr\u00edncipe  Curitiba Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1051-2056","authenticated-orcid":false,"given":"Bonald Cavalcante","family":"de Figueiredo","sequence":"additional","affiliation":[{"name":"Instituto de Pesquisa Pel\u00e9 Pequeno Pr\u00edncipe  Curitiba Brazil"},{"name":"Faculdades Pequeno Pr\u00edncipe  Curitiba Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9166-2146","authenticated-orcid":false,"given":"Lauro Mera","family":"de Souza","sequence":"additional","affiliation":[{"name":"Instituto de Pesquisa Pel\u00e9 Pequeno Pr\u00edncipe  Curitiba Brazil"},{"name":"Faculdades Pequeno Pr\u00edncipe  Curitiba Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,2,2]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2004.08.085"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2013-1029"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.14740\/jocmr3503w"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00268-005-0329-x"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.46.3711"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-1-4160-5583-9.00106-4"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-18-0608"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-11-0557"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.mph.0000212965.52759.1c"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0142(19981115)83:10<2194::AID-CNCR19>3.0.CO;2-3"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1590\/S0004-27302004000500010"},{"issue":"6","key":"e_1_2_10_13_1","first-page":"2234","article-title":"Low\u2010dose monitored mitotane treatment achieves the therapeutic range with manageable side effects in patients with adrenocortical cancer","volume":"85","author":"Terzolo M","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1677\/ERC-08-0103"},{"issue":"5","key":"e_1_2_10_15_1","first-page":"387","article-title":"Severe adrenal cortical atrophy (cytotoxic) and hepatic damage produced in dogs by feeding 2,2\u2010bis (parachlorophenyl)\u20101,1\u2010dichloroethane DDD or TDE","volume":"48","author":"Nelson AA","year":"1949","journal-title":"Arch Pathol (Chic)"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplegacy.1954.176.3.374"},{"key":"e_1_2_10_17_1","first-page":"341","article-title":"Regression of adrenal cancer and suppression of adrenal function in men by o,p'\u2010DDD","volume":"72","author":"Bergenstal DM","year":"1959","journal-title":"Trans Assoc Am Physicians"},{"issue":"10","key":"e_1_2_10_18_1","first-page":"13","article-title":"Understanding mitotane mode of action","volume":"68","author":"Waszut U","year":"2017","journal-title":"J Physiol Pharmacol"},{"issue":"02","key":"e_1_2_10_19_1","first-page":"109","article-title":"Advanced Adrenocortical Carcinoma \u2013 What to do when First\u2010Line Therapy Fails?","volume":"127","author":"Megerle F","year":"2018","journal-title":"Exp Clin Endocrinol Diabetes"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2020.101415"},{"key":"e_1_2_10_21_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2018\/9362108","article-title":"Benefits of Adjuvant Mitotane after Resection of Adrenocortical Carcinoma: A Systematic Review and Meta\u2010Analysis","volume":"2018","author":"Tang Y","year":"2018","journal-title":"Biomed Res Int"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-018-0424-9"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1677\/erc.1.01025"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1200966"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1993.11.1.161"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0142(20000301)88:5<1159::AID-CNCR28>3.0.CO;2-R"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.10487"},{"key":"e_1_2_10_28_1","unstructured":"PubChem. National Library of Medicine.https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/4211. Accessed in October 20 2020."},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(84)90503-3"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2013.07.023"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00258213"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0b013e3283606cb2"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0000000000000102"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2010-2676"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00265384"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2006.04.005"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.01109105"},{"issue":"3","key":"e_1_2_10_38_1","first-page":"1319","article-title":"Cytochrome P450\u2010Catalyzed Binding of 3\u2010Methylsulfonyl\u2010DDE and o,p'\u2010DDD in Human Adrenal Zona fasciculata\/Reticularis","volume":"87","author":"Lindhe \u00d6","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-15-0946"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1210\/JC.2015-2080"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00685956"},{"key":"e_1_2_10_42_1","first-page":"671","article-title":"Possible mechanism and treatment of o,p'DDD\u2010induced hypercholesterolaemia","volume":"84","author":"Maher VM","year":"1992","journal-title":"Q J Med"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chemosphere.2005.04.100"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chemosphere.2009.03.050"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.3109\/00498250903470230"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2017.07.008"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.2174\/1871526517666170329123845"},{"issue":"3","key":"e_1_2_10_48_1","first-page":"127","article-title":"Metabolism and covalent binding of 1\u2010(o\u2010chlorophenyl)\u20101\u2010(p\u2010chlorophenyl)\u20102,2\u2010dichloroethane (o,p'\u2010DDD). Correlation between adrenocorticolytic activity and metabolic activation by adrenocortical mitochondria","volume":"8","author":"Martz F","year":"1980","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12672-014-0189-7"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2014.11.027"},{"issue":"5","key":"e_1_2_10_51_1","first-page":"482","article-title":"The in vitro metabolism of 1\u2010(o\u2010chlorophenyl)\u20101\u2010(p\u2010chlorophenyl)\u20102,2\u2010dichloroethane (o,p'\u2010DDD) by dog adrenal mitochondria and metabolite covalent binding to mitochondrial macromolecules: a possible mechanism for the adrenocorticolytic effect","volume":"5","author":"Martz F","year":"1977","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/0009-2797(89)90063-X"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2012.1244"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.surg.2016.11.036"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0105855"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12020359"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12272-017-0986-y"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.30.2.113"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-10-0956"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-014-0517-2"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1080\/009841098159187"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-18-0342"},{"issue":"1","key":"e_1_2_10_63_1","first-page":"15","article-title":"Metabolism of 1\u2010(0\u2010chlorophenyl)\u20101\u2010(p\u2010chlorophenyl)\u20102,2\u2010dichloroethane (o,p'\u2010DDD) in rats","volume":"3","author":"Reif VD","year":"1975","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1159\/000136627"},{"issue":"1","key":"e_1_2_10_65_1","first-page":"13","article-title":"Metabolism of o,p'\u2010DDD (mitotane) in human and animals. Actual notions and practical deductions","volume":"38","author":"Touitou Y","year":"1977","journal-title":"Ann Endocrinol (Paris)"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2012.04.007"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2012-1159"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.18968"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0196931"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.2217\/pgs.12.116"},{"key":"e_1_2_10_71_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2015-1367"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2014.09.008"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/624962"},{"key":"e_1_2_10_74_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2015-2052"},{"key":"e_1_2_10_75_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.01177.x"},{"key":"e_1_2_10_76_1","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-12-0368"},{"key":"e_1_2_10_77_1","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-13-0150"},{"key":"e_1_2_10_78_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-2385-4"},{"key":"e_1_2_10_79_1","doi-asserted-by":"publisher","DOI":"10.1677\/ERC-07-0003"},{"key":"e_1_2_10_80_1","doi-asserted-by":"publisher","DOI":"10.1385\/MO:21:2:167"},{"key":"e_1_2_10_81_1","doi-asserted-by":"publisher","DOI":"10.2169\/internalmedicine.8216-16"},{"key":"e_1_2_10_82_1","doi-asserted-by":"publisher","DOI":"10.1530\/EC-19-0510"},{"key":"e_1_2_10_83_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-2639"},{"key":"e_1_2_10_84_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.17.2775"},{"key":"e_1_2_10_85_1","doi-asserted-by":"publisher","DOI":"10.1089\/105072503768499644"},{"key":"e_1_2_10_86_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2011.02.053"},{"key":"e_1_2_10_87_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-17-0452"},{"key":"e_1_2_10_88_1","doi-asserted-by":"publisher","DOI":"10.1016\/0009-2797(88)90028-2"},{"key":"e_1_2_10_89_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-008-0342-6"},{"key":"e_1_2_10_90_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-007-0206-5"},{"key":"e_1_2_10_91_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.1371"},{"key":"e_1_2_10_92_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0030-1261923"},{"key":"e_1_2_10_93_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2009.10.018"},{"key":"e_1_2_10_94_1","doi-asserted-by":"publisher","DOI":"10.2174\/092986712804143376"},{"key":"e_1_2_10_95_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.colsurfb.2011.03.015"},{"key":"e_1_2_10_96_1","doi-asserted-by":"publisher","DOI":"10.3109\/03639040903225083"},{"key":"e_1_2_10_97_1","doi-asserted-by":"publisher","DOI":"10.3109\/10837450.2011.614250"},{"key":"e_1_2_10_98_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2006.05.006"},{"key":"e_1_2_10_99_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-814033-8.00017-5"},{"key":"e_1_2_10_100_1","doi-asserted-by":"publisher","DOI":"10.1002\/mabi.201900178"},{"key":"e_1_2_10_101_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14751"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcp.14721","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bcp.14721","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcp.14721","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T06:14:19Z","timestamp":1693289659000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bcp.14721"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,2]]},"references-count":100,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2021,7]]}},"alternative-id":["10.1111\/bcp.14721"],"URL":"https:\/\/doi.org\/10.1111\/bcp.14721","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.22541\/au.159069174.47481624","asserted-by":"object"}]},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"value":"0306-5251","type":"print"},{"value":"1365-2125","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,2]]}}}