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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

Supelco
(±)-Propranolol hydrochloride, analytical standard
Verapamil hydrochloride, European Pharmacopoeia (EP) Reference Standard
Ondansetron hydrochloride dihydrate, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
(±)-Propranolol hydrochloride, ≥99% (TLC), powder
Sigma-Aldrich
Ondansetron hydrochloride dihydrate, ≥98% (HPLC), powder
Sigma-Aldrich
HEPES buffer solution, 1 M in H2O
Sigma-Aldrich
Quinidine, crystallized, ≥98.0% (dried material, NT)
Sigma-Aldrich
Quinidine, anhydrous
Supelco
Antipyrine, analytical standard
SAFC
HEPES
Supelco
Ondansetron Hydrochloride, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
(±)-Verapamil hydrochloride, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Desloratadine, powder, ≥98% (HPLC)
SAFC
Sodium chloride solution, 5 M
Propranolol hydrochloride, European Pharmacopoeia (EP) Reference Standard
SAFC
HEPES
Ondansetron for TLC system suitability, European Pharmacopoeia (EP) Reference Standard
Ondansetron for LC system suitability, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
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Sodium chloride-35Cl, 99 atom % 35Cl
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Sodium chloride, random crystals, optical grade, 99.9% trace metals basis
Desloratadine, European Pharmacopoeia (EP) Reference Standard
Supelco
HEPES, Pharmaceutical Secondary Standard; Certified Reference Material
USP
Loratadine Related Compound A, United States Pharmacopeia (USP) Reference Standard
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Supelco
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Supelco
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