title: Formation Rate-Limited Pharmacokinetics of Biologically Active Epoxy Transformers of Prodrug Treosulfan.
abstract: A prodrug treosulfan (TREO) is being evaluated in clinical trials as a myeloablative agent before hematopoietic stem cell transplantation. The active derivatives of TREO, monoepoxide (EBDM), and diepoxide (DEB) are formed in a pH-dependent nonenzymatic reaction. The aim of the study was to investigate pharmacokinetics of the TREO epoxy transformers in a rabbit model and explain the causes of low plasma concentrations of EBDM and DEB observed in patients receiving high-dose TREO before hematopoietic stem cell transplantation. New Zealand white rabbits (n = 5 per cohort) received an intravenous infusion of TREO (group I), injection of DEB (group II), and injection of a solution containing EBDM (group III). When EBDM and DEB were administered to the rabbits, they underwent a very rapid elimination (half-life 0.069 and 0.046 h) associated with a high systemic clearance (10.0 and 14.0 L h(-1) kg(-1)). After administration of TREO, the t1/2 of EBDM was statistically equal to the t1/2 of the prodrug (1.6 h). To conclude, after administration of TREO, its epoxy transformers demonstrate a formation-limited elimination. Then EBDM and DEB have the same elimination half-life as TREO, but the levels of EBDM and DEB in the body, including plasma, are much lower than TREO on account of their inherently high clearance.
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 Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poznan 60-781, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kasprzyk
authors.affiliation: Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, Poznan 61-861, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Karbownik
authors.affiliation: Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, Poznan 61-861, Poland.
authors.forename: Edyta
authors.initials: E
authors.lastname: Szałek
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: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics; D002066:Busulfan / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011817:Rabbits; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004852:Epoxy Compounds; D011355:Prodrugs; C018404:treosulfan; D002066:Busulfan
keywords: HPLC; bioanalysis; disposition; elimination; metabolite kinetics; pharmacokinetics; prodrugs