Development of an LC-MS/MS assay to determine plasma pharmacokinetics of the radioprotectant octadecenyl thiophosphate (OTP) in monkeys.
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.
Kosanam
Hari
H
Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Advanced Cancer Detection Center, Samuel Lunenfeld Research Institute, Toronto, ON, Canada.
Ma
Fei
F
He
Hui
H
Ramagiri
Suma
S
Gududuru
Veeresa
V
Tigyi
Gabor J
GJ
Van Rompay
Koen
K
Miller
Duane D
DD
Yates
Charles R
CR
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*
D000440:Butanols; D009943:Organophosphorus Compounds; D011837:Radiation-Protective Agents; C520653:octadecenyl thiophosphate