Brain and plasma exposure profiling in early drug discovery using cassette administration and fast liquid chromatography-tandem mass spectrometry.
A method using reverse phase liquid chromatography-tandem mass spectrometry and cassette administration was developed for in vivo brain and plasma exposure profiling to assist early CNS drug discovery programs. Three to four compounds were grouped in cassettes for dosing and analysis. Compounds in the cassettes were selected to minimize possible analytical interference from each other, as well as from their potential metabolites. In order to improve the confidence of cassette administration, an analogue of the study compounds, with well-established brain penetration data, was included in each cassette as a "biological internal standard". Compounds were administered to rats by intraperitoneal injection and extracted from plasma or brain homogenate by simple protein precipitation. Fast chromatographic separation was achieved by using a short narrow-bore column at a flow rate of 1.0ml/min with a fast gradient. The brain penetration of the compounds was evaluated by comparing their C(max) and AUC values in brain and plasma. This approach rapidly provided early brain penetration and plasma exposure information, thus making more of this data available to teams. Comparing the brain exposures to the EC(50) values (i.e. in vitro potency) of series compounds in the same discovery program provided another dimension of information to select lead compounds for future in vivo assessment. The method described here has been used for providing early brain penetration information in several CNS exploratory and discovery programs.
Zhang
Mei-Yi
MY
Chemical and Screening Sciences, Wyeth Research, CN8000, Princeton, NJ 08543-8000, USA. zhangm@wyeth.com
Kerns
Edward
E
McConnell
Oliver
O
Sonnenberg-Reines
June
J
Zaleska
Margaret M
MM
Steven Jacobsen
J
J
Butera
John
J
Kreft
Anthony
A
D000818:Animals; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry / Q000502:physiology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008297:Male; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000032:analysis / Q000097:blood*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013678:Technology, Pharmaceutical / Q000379:methods*
D004364:Pharmaceutical Preparations