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KMID : 0043320170400080952
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Archives of Pharmacal Research
2017 Volume.40 No. 8 p.952 ~ p.961
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Determination and validation of LJ-2698, a potent human A3 adenosine receptor antagonist, in rat plasma by liquid chromatography-tandem mass spectrometry and its application in pharmacokinetic study
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Lee Jae-Young
Park Ju-Hwan
Kim Ki-Taek
Yu Jin-Ha
Sahu Pramod K.
Kang Nae-Won
Shin Hyeon-Jong
Kim Min-Hwan
Kim Ji-Su
Yoon In-Soo
Jeong Lak-Shin
Kim Dae-Duk
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Abstract
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LJ-2698, a highly potent human A3 adenosine receptor antagonist with nucleoside structure, was designed to have a minimal species dependence. For further pre-clinical studies, analytical method for the detection of LJ-2698 in rat plasma was developed by liquid chromatography-tandem mass. Plasma samples were processed by protein precipitation method with acetonitrile, using losartan as the internal standard (IS). Chromatographic separation was carried out using a Kinetex C18 column (100 × 4.6 mm; 100 A; 2.6 μ) with acetonitrile/water with 0.2% (v/v) formic acid (65:35, v/v) in the isocratic mode at a flow rate of 0.4 mL/min. Mass spectrometric detection in multiple reaction monitoring mode was performed with positive electrospray ionization. The mass transitions of LJ-2698 and IS were m/z 412.3 → 294.1 and m/z 423.1 → 207.2, respectively. The calibration curves were linear in the range 5.00?5000 ng/mL (r2 ≥ 0.998). The lower limit of quantification was established as 5.00 ng/mL. Within- and between-run precisions were <7.01%, as relative standard deviation; and accuracies were in the range 3.37?3.64%, as relative error. The validated method was successfully applied to its pharmacokinetic evaluation after intravenous and oral administration in rats, and the dose-dependent pharmacokinetic behavior of LJ-2698 was elucidated for the first time.
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KEYWORD
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LJ-2698, Adenosine analogues, hA3 AR antagonist, LC?MS/MS, Validation, Pharmacokinetics
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