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  • Utility of cerebrospinal fluid drug concentration as a surrogate for unbound brain concentration in nonhuman primates.

Utility of cerebrospinal fluid drug concentration as a surrogate for unbound brain concentration in nonhuman primates.

Drug metabolism and pharmacokinetics (2014-05-09)
Yoko Nagaya, Yoshitane Nozaki, Kazumasa Kobayashi, Osamu Takenaka, Yosuke Nakatani, Kazutomi Kusano, Tsutomu Yoshimura, Hiroyuki Kusuhara
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.

MATERIALS
Product Number
Brand
Product Description

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