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Investigation of the high partition of YM992, a novel antidepressant, in rat brain ‐ in vitro and in vivo evidence for the high binding in brain and the high permeability at the BBB

Brain extracellular fluid (ECF) concentration of YM992, a novel antidepressant, was determined using brain microdialysis to investigate the high partition of this drug to the brain after systemic administration to rats. Plasma, cerebrospinal fluid (CSF), ECF and brain concentrations were determined at the steady‐state after intravenous infusion to rats. The concentration ratio of brain to plasma at the total concentration base was 71.3, while those of ECF to plasma and CSF to plasma at the free concentration base were comparable. The distribution volume in brain was 375 ml/g brain and in vitro binding of YM992 to rat brain was 98.1–98.5%, suggesting a high binding in the brain. The carotid artery injection study showed that the brain uptake index of YM992 was 141%, furthermore, the uptake clearance into brain after i.v. dosing to rats was 0.6 ml/min/g brain, indicating a high permeability at the blood–brain barrier (BBB). These findings suggest that the high partition of YM992 to rat brain is attributed to its high level of binding in the brain as well as its high permeability at the BBB. Copyright © 2002 John Wiley & Sons, Ltd.