title: Activation of Prodrug Treosulfan at pH 7.4 and 37°C Accompanied by Hydrolysis of Its Active Epoxides: Kinetic Studies with Clinical Relevance.
abstract: Treosulfan (TREO), originally registered for treatment of ovarian cancer, is currently being investigated for conditioning prior to hematopoietic stem cell transplantation. TREO is a prodrug, which undergoes a pH- and temperature-dependent two-step conversion to active monoepoxide [S,S-EBDM, (2S,3S)-1,2-epoxybutane-3,4-diol-4-methanesulfonate] and diepoxide [S,S-DEB, (2S,3S)-1,2:3,4-diepoxybutane]. In this paper, the kinetics of the nonenzymatic transformation of TREO at pH 7.4 and 37°C were studied for the first time including the effects of the TREO concentration, buffer concentration, ionic strength, and the presence of NaCl. Transformation of TREO was well described by a kinetic model, which included first-order reactions for TREO activation, that is, TREO → S,S-EBDM → S,S-DEB, and pseudo-first-order reactions for the hydrolytic decomposition of S,S-EBDM and S,S-DEB. In contrast to the two-step activation of TREO, the hydrolysis of epoxides was influenced by electrolytes. In phosphate-buffered saline, decomposition of S,S-EBDM and S,S-DEB (mean half-lives 25.7 and 15.4 h) proceeded much slower than their formation (mean half-lives 1.5 and 3.5 h). In conclusion, the kinetics of the nonenzymatic transformation of TREO in the presence of plasma electrolytes cannot contribute to the very low levels of S,S-EBDM and S,S-DEB observed in patient plasma. The results also indicate that elimination of TREO proceeds primarily via conversion to S,S-EBDM.
authors.affiliation: Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznan 60-781, Poland. Electronic address: michalroman@ump.edu.pl.
authors.forename: Michał
authors.initials: M
authors.lastname: Romański
authors.affiliation: Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences, Poznan 60-780, Poland.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Urbaniak
authors.affiliation: Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences, Poznan 60-780, Poland.
authors.forename: Zenon
authors.initials: Z
authors.lastname: Kokot
authors.affiliation: Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznan 60-781, Poland.
authors.forename: Franciszek K
authors.initials: FK
authors.lastname: Główka
mesh_terms: D002066:Busulfan / Q000031:analogs & derivatives* / Q000737:chemistry; D004573:Electrolytes / Q000737:chemistry; D004852:Epoxy Compounds / Q000737:chemistry*; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D011355:Prodrugs / Q000737:chemistry*
chemical_list: D004573:Electrolytes; D004852:Epoxy Compounds; D011355:Prodrugs; C018404:treosulfan; D002066:Busulfan
keywords: HPLC; mathematical model; metabolite kinetics; pharmacokinetics; prodrugs; refractive index