title: Development and Validation of a High Pressure Liquid Chromatography-UV Method for the Determination of Treosulfan and Its Epoxy Metabolites in Human Plasma and Its Application in Pharmacokinetic Studies.
abstract: Treosulfan (l-threitol-1,4-di-methanesulfonate) is a prodrug of a bifunctional alkylating agent that is being used increasingly in pediatric bone marrow transplantation regimens. The activation pathway is a complex reaction, which consists of two consecutive reactions leading to epoxybutane derivatives which are responsible for DNA alkylation. A simple, sensitive high performance liquid chromatography method for the determination of the sum of treosulfan and its epoxy metabolites by UV detection after derivatization with sodium diethyldithiocarbamate in human plasma was developed and validated. Plasma samples containing treosulfan and epoxy metabolites were converted into thiocarbamate derivative with 10% sodium diethyldithiocarbamate. Dinitrobiphenyl was used as an internal standard. The analysis was carried out using a reversed phase C18 column with a mobile phase consisting of methanol-water (65:35, v/v) at a flow rate of 1 mL/min. The eluent was monitored at 254 nm. The standard calibration curve was established between 2.5 and 50 µg/mL, with a correlation coefficient of 0.9987. Intra- and interday precision and accuracy of the method was <8% and met the analytical criteria. Pharmacokinetic parameters were determined in six children who received intravenous treosulfan (dose range 12-24 g/m(2)) in combination with fludarabine prior to blood or marrow transplantation.
authors.affiliation: Department of Biochemistry, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia Department of Oncology, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia Discipline of Paediatrics and Child Health, The University of Sydney, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia.
authors.forename: Sundar R
authors.initials: SR
authors.lastname: Koyyalamudi
authors.affiliation: Department of Biochemistry, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia.
authors.forename: Unnikrishnan
authors.initials: U
authors.lastname: Kuzhiumparambil
authors.affiliation: Department of Biochemistry, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia Department of Oncology, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia christa.nath@health.nsw.gov.au.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Nath
authors.affiliation: Discipline of Paediatrics and Child Health, The University of Sydney, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia Children's Cancer Research Unit, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Byrne
authors.affiliation: Division of Oncology, Royal Children's Hospital, Brisbane, QLD 4029, Australia.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Fraser
authors.affiliation: Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW 2031, Australia Women's & Children's Health, Faculty of Medicine, University of New South Wales, Kensington, NSW 2052, Australia.
authors.forename: Tracey A
authors.initials: TA
authors.lastname: O'Brien
authors.affiliation: Department of Biochemistry, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia Discipline of Paediatrics and Child Health, The University of Sydney, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia.
authors.forename: John W
authors.initials: JW
authors.lastname: Earl
authors.affiliation: Department of Oncology, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia Discipline of Paediatrics and Child Health, The University of Sydney, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Shaw
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001711:Biotransformation; D001713:Biphenyl Compounds / Q000032:analysis / Q000737:chemistry; D002066:Busulfan / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid / Q000379:methods / Q000592:standards*; D056148:Chromatography, Reverse-Phase / Q000379:methods / Q000592:standards*; D004050:Ditiocarb / Q000737:chemistry; D004852:Epoxy Compounds / Q000097:blood* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D000432:Methanol; D011355:Prodrugs / Q000032:analysis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012015:Reference Standards; D012997:Solvents; D014740:Vidarabine / Q000031:analogs & derivatives / Q000097:blood; D014867:Water
chemical_list: D001713:Biphenyl Compounds; D004852:Epoxy Compounds; D011355:Prodrugs; D012997:Solvents; D014867:Water; D004050:Ditiocarb; C018404:treosulfan; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine; D000432:Methanol