Abstract
Previous publications suggest that interstitial fluid compound concentrations (CISF) best determine quantitative neurotherapeutic pharmacology relationships, although confirming large animal CISF remains elusive. Therefore, this work primarily evaluated using respective acute dose, rat-derived unbound brain compound concentration-to-unbound plasma compound concentration ratios (Cb,u/Cp,u) to project accurately dog and nonhuman primate (nhp) Cb,u, a CISF surrogate, from measured Cp,u for the highly permeable non-P-glycoprotein substrates N-{(3R,4S)-3-[4-(5-cyano-2-thienyl)phenyl]tetrahydro-2H-pyran-4-yl}propane-2-sulfonamide (PF-4778574) and [4-chloro-5-fluoro-2-(3-methoxy-2-methyl-phenoxy)-benzyl]-methylamine (CE-157119) and the P-glycoprotein substrates risperidone and 9-hydroxyrisperidone. First, in rats, it was determined for eight of nine commercial compounds that their single-dose-derived Cb,u/Cp,u were ≤2.5-fold different from their steady-state values; for all nine drugs, their Cb,u/Cp,u were ≤2.5-fold different from their steady-state CISF/Cp,u (Drug Metab Dispos 37:787–793, 2009). Subsequently, PF-4778574, CE-157119 and risperidone underwent rat, dog, and nhp neuropharmacokinetics studies. In large animals at each measured Cp,u, the methodology adequately predicted [estimated mean (95% confidence interval) of 1.02 (0.80, 1.29)] the observed Cb,u for PF-4778574 and CE-157119 but underpredicted [0.17 (0.12, 0.22)] Cb,u for risperidone and 9-hydroxyrisperidone. The data imply that forecasting higher species Cb,u from a measured Cp,u and rat acute dose-determined Cb,u:Cp,u is of high confidence for nonefflux transporter substrates that show net passive diffusion (PF-4778574) or net active influx (CE-157119) at the blood-brain barrier in rats. However, this methodology appears ineffective for correctly predicting large animal Cb,u for P-glycoprotein substrates (risperidone and 9-hydroxyrisperidone) because of their apparently much greater Cp,u-favoring Cb,u:Cp,u asymmetry in rats versus dogs or nhp. Instead, for such P-glycoprotein substrates, large animal-specific cerebrospinal fluid compound concentrations (CCSF) seemingly best represent Cb,u.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
ABBREVIATIONS:
- CNS
- central nervous system
- BBB
- blood-brain barrier
- CSF
- cerebrospinal fluid
- Cp,u
- unbound plasma compound concentration
- ISF
- interstitial fluid
- CISF
- interstitial fluid compound concentration
- CCSF
- cerebrospinal fluid compound concentration
- nhp
- nonhuman primate
- Cb,u
- unbound brain compound concentration
- PGRD
- Pfizer Global Research and Development
- AUC
- area under the matrix compound concentration-time curve
- Cp
- total plasma compound concentration
- fu,p
- fraction of compound unbound in plasma
- fu,b
- fraction of compound unbound in brain homogenate
- Cm
- intracerebral microdialysis-determined interstitial fluid compound concentration
- PF-4778574
- N-{(3R,4S)-3-[4-(5-cyano-2-thienyl)phenyl]tetrahydro-2H-pyran-4-yl}propane-2-sulfonamide
- CE-157119
- [4-chloro-5-fluoro-2-(3-methoxy-2-methyl-phenoxy)-benzyl]-methylamine
- P-gp
- P-glycoprotein
- DPBS
- Dulbecco's phosphate-buffered saline
- HPBCD
- hydroxypropyl β-cyclodextrin
- LC-MS/MS
- liquid chromatography-tandem mass spectrometry
- AUC0-Tlast
- area under the matrix compound concentration-time curve from time 0 to the last time point
- AUC0-∞
- area under the matrix compound concentration-time curve from time 0 to infinity
- AUCTlast-∞
- area under the matrix compound concentration-time curve from the last time point to infinity
- LLOQ
- lower limit of quantification
- Cb,u,obs
- large animal observed unbound brain compound concentration
- Cb,u,pred
- large animal predicted unbound brain compound concentration
- MW
- molecular weight
- CI
- confidence interval
- Bcrp
- breast cancer resistance protein.
- Received April 23, 2012.
- Accepted August 16, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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