title: Investigation of utility of cerebrospinal fluid drug concentration as a surrogate for interstitial fluid concentration using microdialysis coupled with cisternal cerebrospinal fluid sampling in wild-type and Mdr1a(-/-) rats.
abstract: In drug discovery, the cerebrospinal fluid (CSF) drug concentration (CCSF) has been used as a surrogate for the interstitial fluid (ISF) concentration (CISF). However, the CCSF-to-CISF gradient suggested for P-glycoprotein (P-gp) substrates in rodents causes uncertainty in CISF estimations and subsequent pharmacokinetic-pharmacodynamic analyses. To evaluate the utility of CCSF as a surrogate for CISF, this study directly compared the CCSF with the CISF of 12 compounds, including P-gp substrates, under steady-state conditions in wild-type and Mdr1a(-/-) rats using microdialysis coupled with cisternal CSF sampling. In wild-type rats, the ISF-to-unbound plasma (Kp,uu,ISF) and CSF-to-unbound plasma (Kp,uu,CSF) concentration ratios of the P-gp substrates, except for metoclopramide, were lower than those of the non-P-gp substrates, and the Kp,uu,CSF values were within or close to 3-fold of the Kp,uu,ISF values for all the compounds examined. The Kp,uu,CSF values of the selected P-gp substrates increased in Mdr1a(-/-) rats with a similar magnitude to the Kp,uu,ISF values, resulting in the Kp,uu,CSF-to-Kp,uu,ISF ratios being unchanged. These results suggested that P-gp-mediated active efflux at the blood-brain barrier is a major determinant not only for CISF, but also for CCSF, and that CCSF can be used as a surrogate for CISF even for P-gp substrates in rats.
authors.affiliation: Drug Metabolism and Pharmacokinetics Japan, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki, 300-2635, Japan. Electronic address: y-nagaya@hhc.eisai.co.jp.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nagaya
authors.affiliation: Drug Metabolism and Pharmacokinetics Japan, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki, 300-2635, Japan.
authors.forename: Yoshitane
authors.initials: Y
authors.lastname: Nozaki
authors.affiliation: Modeling & Simulation, Clinical Pharmacology, Eisai Co., Ltd., 4-6-10 Koishikawa, Bunkyo-ku, Tokyo 112-8088, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takenaka
authors.affiliation: Drug Metabolism and Pharmacokinetics Japan, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki, 300-2635, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Watari
authors.affiliation: Drug Metabolism and Pharmacokinetics Japan, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki, 300-2635, Japan.
authors.forename: Kazutomi
authors.initials: K
authors.lastname: Kusano
authors.affiliation: Drug Metabolism and Pharmacokinetics Japan, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki, 300-2635, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yoshimura
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-003, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism*; D008297:Male; D017551:Microdialysis / Q000379:methods; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations; C095122:multidrug resistance protein 3
keywords: Brain; Central nervous system; Cerebrospinal fluid; Drug discovery; Interstitial fluid; Microdialysis; P-glycoprotein; Rats