Pharmacokinetics of the adrenocorticolytic compounds 3-methylsulphonyl-DDE and o,p'-DDD (mitotane) in Minipigs.
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.
Hermansson
Veronica
V
Department of Environmental Toxicology, Uppsala University, Norbyvägen 18 A, 752 36 Uppsala, Sweden.
Cantillana
Tatiana
T
Hovander
Lotta
L
Bergman
Ake
A
Ljungvall
Karl
K
Magnusson
Ulf
U
Törneke
Karolina
K
Brandt
Ingvar
I
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
D018931:Antineoplastic Agents, Hormonal; D003633:Dichlorodiphenyl Dichloroethylene; C055238:1-chloro-4-(2,2-dichloro-1-(4-chlorophenyl)ethenyl)-3-(methylsulfonyl)benzene; D008939:Mitotane