Abstract |
Palomid 529 (8-(1-Hydroxy-ethyl)-2-methoxy-3-(4-methoxy-benzyloxy)-benzo[c]chromen-6-one), is a novel non-steroidal small-molecule drug, which inhibits both mTORC1 and mTORC2 assembly, and elicits both anti-angiogenic and direct anti- tumor effects in vivo. We have developed and validated a sensitive and selective method for the quantification of Palomid 529 in human and mouse plasma and in a range of mouse tissue samples. Sample pretreatment involved liquid-liquid extraction with tert-butyl methyl ether yielding a recovery of >75%. Palomid 529 and the internal standard Palomid 545 were separated using a GraceSmart RP18 column (2.1 mm × 150 mm) packed with 5 μm C-18 material and a mobile phase comprised of 50% (v/v) acetonitrile and 50% (v/v) water delivered at a flow rate of 0.2 ml/min, and were detected by UV absorbance at a wavelength of 315 nm. Within the linear range of the calibration curve (10-10,000 ng/ml), acceptable accuracy and precision was achieved for all tested matrices. The validation results show that the method was selective and reproducible. Palomid 529 was stable in plasma upon 3 repeated freeze-thaw cycles and during storage for up to 24h at ambient temperature. However, pre-treated samples waiting for HPLC analyses need to be kept under dimmed light conditions at ambient temperature since a significant degradation of both Palomid 529 and Palomid 545 was observed when exposed to light. A pilot pharmacokinetic study in mice demonstrated the applicability of this method for pharmacokinetic purposes. Even at a low dose of 5.4 mg/kg this assay was still sensitive enough to determine the drug concentration in plasma samples obtained up to 24h after administration.
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Authors | Fan Lin, David Sherris, Jos H Beijnen, Olaf Van Tellingen |
Journal | Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
(J Chromatogr B Analyt Technol Biomed Life Sci)
Vol. 879
Issue 32
Pg. 3823-31
(Dec 15 2011)
ISSN: 1873-376X [Electronic] Netherlands |
PMID | 22100549
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011. Published by Elsevier B.V. |
Chemical References |
- Antineoplastic Agents
- Benzopyrans
- palomid 529
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Topics |
- Animals
- Antineoplastic Agents
(analysis, blood, chemistry)
- Benzopyrans
(analysis, blood, chemistry)
- Brain Chemistry
- Chromatography, High Pressure Liquid
(methods)
- Drug Stability
- Humans
- Kidney
(chemistry)
- Linear Models
- Liquid-Liquid Extraction
- Liver
(chemistry)
- Lung
(chemistry)
- Mice
- Myocardium
(chemistry)
- Reproducibility of Results
- Sensitivity and Specificity
- Spleen
(chemistry)
- Temperature
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