title: Utility of cerebrospinal fluid drug concentration as a surrogate for unbound brain concentration in nonhuman primates.
abstract: In central nervous system drug discovery, cerebrospinal fluid (CSF) drug concentration (C(CSF)) has been widely used as a surrogate for unbound brain concentrations (C(u,brain)). However, previous rodent studies demonstrated that when drugs undergo active efflux by transporters, such as P-glycoprotein (P-gp), at the blood-brain barrier, the C(CSF) overestimates the corresponding C(u,brain). To investigate the utility of C(CSF) as a surrogate for interstitial fluid (ISF) concentration (C(ISF)) in nonhuman primates, this study simultaneously determined the C(CSF) and C(ISF) of 12 compounds, including P-gp substrates, under steady-state conditions in cynomolgus monkeys using intracerebral microdialysis coupled with cisternal CSF sampling. Unbound plasma concentrations of non- or weak P-gp substrates were within 2.2-fold of the C(ISF) or C(CSF), whereas typical P-gp substrates (risperidone, verapamil, desloratadine, and quinidine) showed ISF-to-plasma unbound (K(p,uu,ISF)) and CSF-to-plasma unbound concentration ratios (K(p,uu,CSF)) that were appreciably lower than unity. Although the K(p,uu,CSF) of quinidine, verapamil, and desloratadine showed a trend of overestimating the K(p,uu,ISF), K(p,uu,CSF) showed a good agreement with K(p,uu,ISF) within 3-fold variations for all compounds examined. C(u,brain) of some basic compounds, as determined using brain homogenates, overestimated the C(ISF) and C(CSF). Therefore, C(CSF) could be used as a surrogate for C(ISF) in nonhuman primates.
authors.affiliation: Drug Metabolism and Pharmacokinetics Japan, Eisai Product Creation Systems, Eisai Co., Ltd.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nagaya
authors.forename: Yoshitane
authors.initials: Y
authors.lastname: Nozaki
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Osamu
authors.initials: O
authors.lastname: Takenaka
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Nakatani
authors.forename: Kazutomi
authors.initials: K
authors.lastname: Kusano
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yoshimura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D008252:Macaca fascicularis / Q000134:cerebrospinal fluid* / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D004364:Pharmaceutical Preparations / Q000032:analysis* / Q000134:cerebrospinal fluid*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D004364:Pharmaceutical Preparations