title: Penetration of Treosulfan and its Active Monoepoxide Transformation Product into Central Nervous System of Juvenile and Young Adult Rats.
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.
authors.affiliation: 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.).
authors.forename: Michał
authors.initials: M
authors.lastname: Romański
authors.affiliation: 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.).
authors.forename: Joachim
authors.initials: J
authors.lastname: Baumgart
authors.affiliation: 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.).
authors.forename: Sonja
authors.initials: S
authors.lastname: Böhm
authors.affiliation: 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.) glowka@ump.edu.pl.
authors.forename: Franciszek K
authors.initials: FK
authors.lastname: Główka
mesh_terms: D000367:Age Factors; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002066:Busulfan / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D004852:Epoxy Compounds / Q000378:metabolism*; D005260:Female; D008297:Male; D011247:Pregnancy; D051381:Rats
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004852:Epoxy Compounds; C018404:treosulfan; D002066:Busulfan