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) andyoungadult 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 TREOwas 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.