title: Pharmacokinetics of the adrenocorticolytic compounds 3-methylsulphonyl-DDE and o,p'-DDD (mitotane) in Minipigs.
abstract: The pharmacokinetics of the adrenocorticolytic drug candidate 3-Methylsulphonyl-DDE (3-MeSO2-DDE) and the anticancer drug o,p'-DDD (mitotane) were studied in Göttingen minipigs. The animals were given 3-MeSO2-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-MeSO2DDE. o,p'-DDD plasma concentrations declined rapidly to low levels during 4 days. 3-MeSO2-DDE also decreased rapidly, but remained at high concentrations throughout the study. In fat, 3-MeSO2-DDE reached about 25-fold higher levels than o,p'-DDD at 30 days, and both substances were eliminated slowly from this tissue. 3-MeSO2-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-MeSO2-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-MeSO2-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.
authors: Department of Environmental Toxicology, Uppsala University, Norbyvägen 18 A, 752 36 Uppsala, Sweden.
authors: Veronica
authors: V
authors: Hermansson
authors: Tatiana
authors: T
authors: Cantillana
authors: Lotta
authors: L
authors: Hovander
authors: Ake
authors: A
authors: Bergman
authors: Karl
authors: K
authors: Ljungvall
authors: Ulf
authors: U
authors: Magnusson
authors: Karolina
authors: K
authors: Törneke
authors: Ingvar
authors: I
authors: Brandt
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000302:Adrenal Cortex / Q000187:drug effects*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D002849:Chromatography, Gas; D003627:Data Interpretation, Statistical; D003633:Dichlorodiphenyl Dichloroethylene / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004563:Electrochemistry; D008099:Liver / Q000378:metabolism; D008939:Mitotane / Q000493:pharmacokinetics*; D050151:Subcutaneous Fat / Q000378:metabolism; D013552:Swine; D013556:Swine, Miniature; D014018:Tissue Distribution
chemical_list: D018931:Antineoplastic Agents, Hormonal; D003633:Dichlorodiphenyl Dichloroethylene; C055238:1-chloro-4-(2,2-dichloro-1-(4-chlorophenyl)ethenyl)-3-(methylsulfonyl)benzene; D008939:Mitotane