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Research ArticleArticle

Penetration of Treosulfan and its Active Monoepoxide Transformation Product into Central Nervous System of Juvenile and Young Adult Rats

Michał Romański, Joachim Baumgart, Sonja Böhm and Franciszek K. Główka
Drug Metabolism and Disposition December 2015, 43 (12) 1946-1954; DOI: https://doi.org/10.1124/dmd.115.066050
Michał Romański
Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznan, Poland (M.R., F.K.G.); and medac GmbH, Wedel, Germany (J.B., S.B.)
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Joachim Baumgart
Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznan, Poland (M.R., F.K.G.); and medac GmbH, Wedel, Germany (J.B., S.B.)
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Sonja Böhm
Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznan, Poland (M.R., F.K.G.); and medac GmbH, Wedel, Germany (J.B., S.B.)
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Franciszek K. Główka
Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznan, Poland (M.R., F.K.G.); and medac GmbH, Wedel, Germany (J.B., S.B.)
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Abstract

Treosulfan (TREO) is currently investigated as an alternative treatment of busulfan in conditioning before hematopoietic stem cell transplantation. The knowledge of the blood-brain barrier penetration of the drug is still scarce. In this paper, penetration of TREO and its active monoepoxide (S,S-EBDM) and diepoxide (S,S-DEB) into the CNS was studied in juvenile (JR) and young adult rats (YAR) for the first time. CD rats of both sexes (n = 96) received an intravenous dose of TREO 500 mg/kg b.wt. Concentrations of TREO, S,S-EBDM, and S,S-DEB in rat plasma, brain, and cerebrospinal fluid (CSF, in YAR only) were determined by validated bioanalytical methods. Pharmacokinetic calculations were performed in WinNonlin using a noncompartmental analysis and statistical evaluation was done in Statistica software. In male JR, female JR, male YAR, and female YAR, the brain/plasma area under the curve (AUC) ratio for unbound TREO was 0.14, 0.17, 0.10, and 0.07 and for unbound S,S-EBDM, it was 0.52, 0.48, 0.28, and 0.22, respectively. The CSF/plasma AUC ratio in male and female YAR was 0.12 and 0.11 for TREO and 0.66 and 0.64 for S,S-EBDM, respectively. Elimination rate constants of TREO and S,S-EBDM in all the matrices were sex-independent with a tendency to be lower in the JR. No quantifiable levels of S,S-DEB were found in the studied samples. TREO and S,S-EBDM demonstrated poor and sex-independent penetration into CNS. However, the brain exposure was greater in juvenile rats, so very young children might potentially be more susceptible to high-dose TREO-related CNS exposure than young adults.

Footnotes

    • Received June 23, 2015.
    • Accepted September 30, 2015.
  • The studies were financially supported by medac GmbH (Wedel, Germany).

  • The results of the work were presented in abstract form at the following conference: Główka F, Romański M, Baumgart J, Böhm S (2014) Blood-brain barrier penetration of treosulfan and its biologically active epoxides in juvenile and young adult rats. 40th Annual Meeting of the European Group for Blood and Marrow Transplantation; 2014 Mar 30–Apr 2; Milan, Italy.

  • dx.doi.org/10.1124/dmd.115.066050.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (12)
Drug Metabolism and Disposition
Vol. 43, Issue 12
1 Dec 2015
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Research ArticleArticle

Penetration of Treosulfan and Its Monoepoxide into CNS

Michał Romański, Joachim Baumgart, Sonja Böhm and Franciszek K. Główka
Drug Metabolism and Disposition December 1, 2015, 43 (12) 1946-1954; DOI: https://doi.org/10.1124/dmd.115.066050

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Research ArticleArticle

Penetration of Treosulfan and Its Monoepoxide into CNS

Michał Romański, Joachim Baumgart, Sonja Böhm and Franciszek K. Główka
Drug Metabolism and Disposition December 1, 2015, 43 (12) 1946-1954; DOI: https://doi.org/10.1124/dmd.115.066050
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