Archives of Pharmacal Research 2015-06-01

In vitro permeability, pharmacokinetics and brain uptake of WAY-100635 and FCWAY in rats using liquid chromatography electrospray ionization tandem mass spectrometry.

Zhi Zheng, So Hee Im, Byung Hoi Lee, Hyewon Seo, Myung Ae Bae, Sung-Hoon Ahn

Index: Arch. Pharm. Res. 38 , 1072-9, (2015)

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Abstract

Positron emission tomography (PET) is a sensitive non-invasive imaging technique. To reduce imaging measurements of defects, there is a demand for proper LC-ESI-MS/MS method to carry out with its specificity and sensitivity. This study describes a rapid and simple liquid chromatography electrospray ionization tandem-MS/MS (LC-ESI-MS/MS) method for determination of both PET tracers: N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (WAY-100635) and 4-fluoro-N-[2-[4-(2-methoxylphenyl)-1-piperazino]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (FCWAY). Both target compounds were prepared by one-step protein precipitation with acetonitrile and methanol (1:1, v/v), and analyzed using a C18 column. This simple method has an excellent linearity, selectivity and sensitivity. Precision and accuracy values for the intra-day and inter-day validation were below 12%. The limit of quantification (LOQ) for both target compounds was defined as 1 ng/mL in plasma and 5 ng/mL in brain homogenate. The stability of both compounds is considered stable under a various experimental conditions. The in vitro MDR-MDCK cell permeability showed the both compounds have high permeability (Papp, A→B ≥ 20 × 10(-6 )cm/s) and low efflux ratio (≤2.0). Brain to blood (AUCbrain/AUCblood) distribution ratios in rats were 3.15 ± 0.42 for WAY-100635 and 2.20 ± 0.34 for FCWAY, respectively, and these results suggest that LC-ESI-MS/MS method might be a supplementary way for the identifying and understanding of radiopharmaceuticals.