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Plasma and cerebrospinal fluid (CSF) pharmacokinetics of CP‐457,920, a selective alpha 5 GABA‐A receptor inverse agonist in young, healthy volunteers
Author(s) -
Bednar M.,
Chieffo C.,
Morse T.,
Duplin M.,
Gibbs M. A.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.115
Subject(s) - cmax , pharmacokinetics , cerebrospinal fluid , pharmacology , chemistry , microdialysis , inverse agonist , agonist , efflux , medicine , receptor , endocrinology , extracellular , biochemistry
Background CP‐457,920 is a selective α5 GABA A receptor inverse agonist studied for the treatment of dementia in Alzheimer's Disease. In vitro , the compound has a potent K i of ~ 1 ng/mL for the α5 GABA A receptor and is a substrate for efflux transporters. However, preclinical microdialysis studies in rats have shown an extracellular fluid (ECF) to CSF ratio that approaches unity. Objectives To estimate CNS penetration of CP‐457,920 after multiple oral dose administration to healthy young adult subjects as measured by the CSF concentration and the CSF to unbound plasma concentration ratio at steady‐state. Methods CP‐457,920 was administered 120 mg BID for 4 days to 6 young healthy volunteers. On day 4 plasma was collected at just prior to dosing and at 1, 2, 3, 4, 6, 8 and 12 hours after dosing. A CSF sample was collected at approximately 4 hours post dose. Results CP‐457,920 was quantifiable in the CSF of all 6 subjects at 4 hours post dose. The CP‐457,920 CSF/unbound concentration ratio was on average approximately 6‐fold less than unity. Despite this disequilibrium, approximately 75% receptor occupancy would be projected at C max in healthy volunteers. Conclusions At steady‐state, CP‐457,920 CSF penetration was observed at concentrations greater than the in vitro receptor K i . The CSF/unbound plasma disequilibrium may be due to low permeability and/or P‐gp mediated efflux. Clinical Pharmacology & Therapeutics (2004) 75 , P30–P30; doi: 10.1016/j.clpt.2003.11.115