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Pharmacokinetics of the adrenocorticolytic compounds 3-methylsulphonyl-DDE and o,p'-DDD (mitotane) in Minipigs.
Stockholm University, Faculty of Science, Department of Environmental Chemistry.
Stockholm University, Faculty of Science, Department of Environmental Chemistry.
Stockholm University, Faculty of Science, Department of Environmental Chemistry.
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2008 (English)In: Cancer Chemother Pharmacol, ISSN 0344-5704, Vol. 61, no 2, 267-274 p.Article in journal (Other academic) Published
Abstract [en]

The pharmacokinetics of the adrenocorticolytic drug candidate 3-Methylsulphonyl-DDE (3-MeSO(2)-DDE) and the anticancer drug o,p'-DDD (mitotane) were studied in Göttingen minipigs. The animals were given 3-MeSO(2)-DDE or o,p'-DDD as single oral doses (30 mg/kg). Concentrations in plasma and subcutaneous fat were measured by gas chromatography at different time points during 180 days. Maximal plasma concentrations appeared within 24 h for both compounds, but were about 2 times higher for 3-MeSO(2)-DDE. o,p'-DDD plasma concentrations declined rapidly to low levels during 4 days. 3-MeSO(2)-DDE also decreased rapidly, but remained at high concentrations throughout the study. In fat, 3-MeSO(2)-DDE reached about 25-fold higher levels than o,p'-DDD at 30 days, and both substances were eliminated slowly from this tissue. 3-MeSO(2)-DDE liver concentrations were about 18-fold higher than those in plasma at 180 days. In contrast, o,p'-DDD liver and plasma levels were about equal at 180 days. o,p'-DDD had roughly 45 times larger CL/F than 3-MeSO(2)-DDE, confirming that the elimination of this compound was more rapid. Both compounds were characterised by their localisation and retention in fat tissue, and the individual size of the fat stores clearly determined the plasma concentrations. It is concluded that although 3-MeSO(2)-DDE is an interesting candidate for therapeutic use due to its potential characteristics to specifically target adrenocortical tumour cells the slow elimination of the compound might make it challenging to design appropriate dosage regimes.

Place, publisher, year, edition, pages
2008. Vol. 61, no 2, 267-274 p.
URN: urn:nbn:se:su:diva-17536ISI: 000251009400009PubMedID: 17431626OAI: diva2:184057
Available from: 2007-12-03 Created: 2007-12-03 Last updated: 2011-01-10Bibliographically approved
In thesis
1. Toxicologically important DDT metabolites: Synthesis, enantioselective analysis and kinetics
Open this publication in new window or tab >>Toxicologically important DDT metabolites: Synthesis, enantioselective analysis and kinetics
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

DDT was extensively and globally used as a pesticide in agriculture and for malaria vector control from the 1940’s until the 1970’s. Due to its heavy use, DDT became ubiquitously distributed throughout the environment. DDT and several DDT metabolites are persistent organic pollutants. Two DDT metabolites, 3-MeSO2-DDE and o,p’-DDD have been proved to be tissue specific toxicants in the adrenal cortex. They are bioactivated to reactive intermediates which bind covalently to the adrenal cortex causing cell death. Due to its tissue specific toxicity o,p’-DDD has been used as a chemotherapy drug for adrenal cancer in humans. The efficacy and potency is however low and o,p’-DDD treatment is associated with serious side effects. 3-MeSO2-DDE has been suggested as a potential alternative therapeutic agent.

A key aim of this thesis has been to improve the understanding of the kinetics of the two adrenocorticolytic compounds o,p’-DDD, its two enantiomers and 3-MeSO2-DDE. To meet this objective chemical synthesis and enantioselective analysis were required. Furthermore, in vitro toxicity of o,p’-DDD enantiomers and diastereomers were performed.

An 11 step synthesis of 3-SH-DDE has been developed to promote both labelled and unlabelled synthesis of 3-alkylsulfonyl-DDE. Toxicokinetic studies showed that 3-MeSO2-DDE and o,p’-DDD were accumulated in tissues and retained in adipose tissue in minipigs. 3-MeSO2-DDE however had a twice as long biological t1/2 and a considerably lower Vd compared to o,p’-DDD. Suckling offspring were more exposed to 3-MeSO2-DDE than their mothers who were given 3-MeSO2-DDE orally. Interindividual differences in enantiomer kinetics in minipigs were observed suggesting polymorphism among the minipigs. Preparative isolation of the o,p’-DDD enantiomers is presented allowing determination of the absolute structures of the o,p’-DDD enantiomers by X-ray. The pure enantiomer of o,p’-DDD showed significant differences in toxicity in human adrenocortical cells.

Place, publisher, year, edition, pages
Stockholm: Department of Environmental Chemistry, Stockholm Univerisity , 2009. 55 p.
o, p'-DDD, 3-Methylsulfonyl-DDE, adrenocorticolytic compounds, chiral
National Category
Environmental Sciences
Research subject
Environmental Chemistry
urn:nbn:se:su:diva-26952 (URN)978-91-7155-829-9 (ISBN)
Public defence
2009-05-29, Magnélisalen, Svante Arrhenius väg 12 A, Stockholm, 10:00 (Swedish)
Available from: 2009-05-08 Created: 2009-04-21 Last updated: 2009-04-23Bibliographically approved

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