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Sample pooling to enhance throughput of brain penetration study.
J P Atherton1, T J Van Noord, B S Kuo
1Department of Drug Metabolism, Pfizer Central Research, Groton, CT 06340, USA.
Journal of Pharmaceutical and Biomedical Analysis
|March 7, 2000
Summary
Sample pooling accelerates pharmacokinetic screening of NK1 receptor antagonists. This method efficiently assessed brain penetration for six compounds in rats, identifying CAM 6108 as the most brain-penetrant.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Neuroscience Research
- Analytical Chemistry
Background:
- High-throughput screening generates numerous prelead compounds requiring rapid kinetic characterization.
- Traditional single-compound bioanalysis limits productivity in pharmacokinetic screening.
- Sample pooling offers a solution to expedite analysis without complex cocktail dosing.
Purpose of the Study:
- To demonstrate the application of sample pooling for expedited pharmacokinetic screening.
- To assess the brain penetration of six NK1 receptor antagonists in rats.
- To validate sample pooling as an efficient bioanalytical strategy.
Main Methods:
- Individual intravenous dosing of six NK1 receptor antagonists in rats.
- Pooling of plasma and brain homogenate samples from identical time points into two groups.
- Quantification of drug compounds using a validated HPLC/fluorescence method with modified gradient.
- Calculation of brain penetration via brain/plasma AUC ratios.
Main Results:
- Plasma assay precision and accuracy for all compounds were within acceptable limits (< or =4.7% and +/-9.8%).
- Brain homogenate assay accuracy for all compounds was within +/-7.0%.
- CAM 6108 showed the greatest brain penetration, followed by CAM 6122, CAM 6121, CAM 5825, CAM 6182, and CAM 6178.
Conclusions:
- Sample pooling significantly expedites pharmacokinetic screening and brain penetration assessment.
- This approach allows for efficient characterization of multiple compounds with individualized dosing.
- The method is robust and accurate for analyzing drug concentrations in plasma and brain tissue.