Novel LC-MS/MS assay to quantify D,L-alpha-difluoromethylornithine (DFMO) in mouse plasma.
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D,L-alpha-difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC) that is being investigated to treat cancers such as pediatric neuroblastoma. A novel and sensitive LC-MS/MS assay was developed and validated to quantify DFMO concentrations in support of pre-clinical pharmacokinetic studies in mice. The study was performed using a Shimadzu triple quad LC-MS/MS equipped with an Atlantis HILIC Silica 3 µm 2.1 × 100 mm column, and an isocratic mobile phase (75:25 acetonitrile and 0.2 % formic acid) at a flow rate of 0.5 mL/min. Multiple Reaction Monitoring (MRM) was used to identify the precursor ion (183 m/z) with quantification of daughter ions at transitions of 183 > 120.10, 183 > 166.10, and 183 > 80.05. Plasma standards and quality control samples (20 µL) were processed using protein precipitation with cold acetonitrile. The lower limit of detection (LLOQ) was 5 ng/mL. Assay performance was determined from multiple runs (n = 10) with standards ranging from 250-50,000 ng/mL and three levels of quality control (500, 4000, and 40,000 ng/mL). Standard curves were linear with r2 values between 0.9960 and 0.9999. Quality control samples were stable and exhibited maximum inter-day % bias of ≤3 % and CV% of ≤0.7 %. The assay was successfully applied to an in vivo study to determine the pharmacokinetics of DFMO in athymic nu/nu mice.