title: Development of an LC-MS/MS assay to determine plasma pharmacokinetics of the radioprotectant octadecenyl thiophosphate (OTP) in monkeys.
abstract: Octadecenyl thiophosphate (OTP), a synthetic analogue of the lysophospholipid growth factor lysophosphatidic acid (LPA), significantly reduces mortality following a lethal dose of LD(80/30) radiation exposure in a mouse model of whole-body irradiation. To facilitate dose scaling between species, we developed a novel liquid chromatography/tandem mass spectrometry (LC-MS/MS) for the preclinical pharmacokinetic characterization of OTP in monkeys. Sample extraction was carried out using a butanol based liquid-liquid extraction method. A partially deuterated OTP analogue was used as internal standard (IS). OTP and IS were separated by reversed-phase liquid chromatography on a C-8 column using 10mM ammonium acetate and acetonitrile. A triple quadrupole mass spectrometer operating in the negative electrospray ionization mode with multiple reaction monitoring was used to detect OTP and IS transitions of m/z 363.1-->95.0 and 403.1-->95.0. The method was applied to determine pharmacokinetic parameters in monkeys receiving a single oral OTP dose (3mg/kg). OTP is readily absorbed with a relatively long half-life which supports further preclinical testing of OTP as a radioprotectant in monkeys.
authors: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Advanced Cancer Detection Center, Samuel Lunenfeld Research Institute, Toronto, ON, Canada.
authors: Hari
authors: H
authors: Kosanam
authors: Fei
authors: F
authors: Ma
authors: Hui
authors: H
authors: He
authors: Suma
authors: S
authors: Ramagiri
authors: Veeresa
authors: V
authors: Gududuru
authors: Gabor J
authors: GJ
authors: Tigyi
authors: Koen
authors: K
authors: Van Rompay
authors: Duane D
authors: DD
authors: Miller
authors: Charles R
authors: CR
authors: Yates
mesh_terms: D000818:Animals; D000440:Butanols / Q000737:chemistry; D005591:Chemical Fractionation; D002853:Chromatography, Liquid / Q000379:methods*; D004355:Drug Stability; D005260:Female; D016014:Linear Models; D008253:Macaca mulatta; D009943:Organophosphorus Compounds / Q000097:blood / Q000493:pharmacokinetics*; D011837:Radiation-Protective Agents / Q000032:analysis / Q000493:pharmacokinetics*; D012015:Reference Standards; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D000440:Butanols; D009943:Organophosphorus Compounds; D011837:Radiation-Protective Agents; C520653:octadecenyl thiophosphate