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Pharmacokinetics of the adrenocorticolytic compounds 3-methylsulphonyl-DDE and o,p′-DDD (mitotane) in Minipigs

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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-MeSO2-DDE. 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.

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Acknowledgments

We are grateful to Carola Jansson and Mari Wallbring at the Swedish University of Agricultural Sciences for excellent support and care of the animals. We also thank Lars Ellegaard, Dalmose, Denmark, for valuable advice. Economic support was given by the Foundation for Strategic Environmental Research (Mistra) through the research program NewS, and by the Swedish EPA through the research program ReproSafe.

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Authors and Affiliations

  1. Department of Environmental Toxicology, Uppsala University, Norbyvägen 18 A, 752 36, Uppsala, Sweden

    Veronica Hermansson & Ingvar Brandt

  2. Department of Environmental Chemistry, Stockholm University, 106 91, Stockholm, Sweden

    Tatiana Cantillana, Lotta Hovander & Åke Bergman

  3. Department of Clinical Sciences, Swedish University of Agricultural Sciences, Centre for Reproductive Biology in Uppsala (CRU), Box 7054, 750 07, Uppsala, Sweden

    Karl Ljungvall & Ulf Magnusson

  4. Swedish Medical Products Agency, Box 26, 751 03, Uppsala, Sweden

    Karolina Törneke

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  1. Veronica Hermansson
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  2. Tatiana Cantillana
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  8. Ingvar Brandt
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Correspondence to Ingvar Brandt.

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Hermansson, V., Cantillana, T., Hovander, L. et al. Pharmacokinetics of the adrenocorticolytic compounds 3-methylsulphonyl-DDE and o,p′-DDD (mitotane) in Minipigs. Cancer Chemother Pharmacol 61, 267–274 (2008). https://doi.org/10.1007/s00280-007-0468-x

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