Pharmacokinetics of T0901317 in mouse serum and tissues using a validated UFLC-IT-TOF/MS method.

Journal of pharmaceutical and biomedical analysis(2020)

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摘要
T0901317, a liver X receptors (LXRs) agonist with high-affinity, is widely used to explore the functions of LXRs in various diseases such as atherosclerosis and Alzheimer's disease. However, there is currently little information available about the pharmacokinetics (PK) behavior of T0901317. Here we established a novel ultrafast liquid chromatography-high resolution mass spectrometry method to quantify the concentration of T0901317 in serum, liver, and brain. The chromatographic separation was attained on a C18 (2.1 × 100 mm, 1.8 μm) column using acetonitrile and 0.1 % of formic acid in water as mobile phase operated in gradient elution mode. The mass detection was carried out using negative ions m/z 479.9809 and 322.0882 for T0901317 and internal standard, respectively. The proposed method was fully validated according to the FDA guidelines, and it generally provides good results in terms of linearity (r2 > 0.99), precision (RSD < 18 % and 12 % for LLOQ and other QC levels, respectively), accuracy (between 92.30 % and 108.16 %), and matrix effect (between 86.56 % and 113.81 %). We then for the first time determined and computed the PK parameters of T0901317 in mouse after intraperitoneal administration of a 20 mg/kg dosage. The peak times (Tmax) in serum, liver, and brain were 1.5, 1.5, and 4 h, respectively, while the half-lives (t1/2) were 4.9, 3.3, and 4.5 h, respectively. Taken together, our results provide a significant choice to study the PK property of T0901317, from which the design of the dosing and sampling protocols of LXRs receptor-antagonist experiments employing T0901317 can also benefit.
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