High-throughput pharmacokinetics: cassette dosing.
The profound technological advances that are now occurring early in the drug discovery process have enabled lead identification groups to deliver very large numbers of promising compounds to the project teams responsible for lead optimization and candidate selection. This success has applied significant pressure to the 'traditional' selection processes performed during the preclinical optimization stages of a new medicine, where compounds with the optimal balance of potency, selectivity, safety and pharmacokinetics, are identified for progression using an iterative synthesis and testing process. Thus, the need exists for higher-throughput methods of determining pharmacokinetic parameters to enable rational decisions to be made on large numbers of compounds. Protocols detailing the administration of mixtures of compounds, cassette dosing, to single animals have been used successfully to increase throughput, and, at the same time address ethical considerations by reducing animal usage. Typically, cassettes of up to ten compounds have been administered in one dose via the intravenous or oral routes. The samples produced have then been analyzed by mass spectrometry.
Bayliss
M K
MK
Biomet Division, Glaxo Wellcome R&D, Hertfordshire, SG12 0DP, UK. MKB2621@glaxowellcome.co.uk
Frick
L W
LW