Pharmacokinetics of T0901317 in mouse serum and tissues using a validated UFLC-IT-TOF/MS method
Xinyue Yu1, Huimin Guo2, Hua He3
1Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Ministry of Education, Nanjing, 210009, China; Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
Abstract:
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.
Insights
This study developed a new method to measure T0901317, a liver X receptors (LXRs) agonist, in mice. The findings provide crucial pharmacokinetic data for T0901317, aiding future research on LXR-related diseases.
Area of Science:
- Pharmacology and Toxicology
- Analytical Chemistry
- Biomedical Research
Background:
- T0901317 is a high-affinity agonist for liver X receptors (LXRs), extensively used in research for diseases like atherosclerosis and Alzheimer's.
- Limited pharmacokinetic (PK) data exists for T0901317, hindering optimal experimental design and interpretation.
- Understanding the PK profile of T0901317 is essential for its effective application in preclinical studies.
Purpose of the Study:
- To establish and validate a novel, ultrafast liquid chromatography-high resolution mass spectrometry (LC-HRMS) method for quantifying T0901317.
- To determine the pharmacokinetic parameters of T0901317 in mice following intraperitoneal administration.
- To provide essential PK data to guide the design of dosing and sampling strategies in LXR-related research.
Main Methods:
- Development of an ultrafast LC-HRMS method for T0901317 quantification in serum, liver, and brain matrices.
- Chromatographic separation using a C18 column with a gradient elution of acetonitrile and formic acid in water.
- Mass detection via negative ion mode, with validated linearity, precision, accuracy, and matrix effect according to FDA guidelines.
Main Results:
- The validated LC-HRMS method demonstrated excellent performance characteristics (r² > 0.99, acceptable precision, accuracy, and matrix effect).
- First-time determination of T0901317 PK parameters in mice after a 20 mg/kg intraperitoneal dose.
- Observed peak times (Tmax) of 1.5 h (serum, liver) and 4 h (brain), and half-lives (t1/2) of 4.9 h (serum), 3.3 h (liver), and 4.5 h (brain).
Conclusions:
- A robust and validated LC-HRMS method for T0901317 PK analysis has been successfully developed and applied.
- The determined PK parameters provide critical insights into the disposition of T0901317 in vivo.
- This study offers a valuable tool and data set for researchers investigating LXRs and designing experiments with T0901317.
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