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

Drug Metab Pharmacokinet. 2014;29(5):419-26. doi: 10.2133/dmpk.dmpk-14-rg-026. Epub 2014 May 6.


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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Animals
  • Blood-Brain Barrier / metabolism
  • Brain / metabolism*
  • Macaca fascicularis / cerebrospinal fluid*
  • Macaca fascicularis / metabolism*
  • Male
  • Microdialysis
  • Pharmaceutical Preparations / analysis*
  • Pharmaceutical Preparations / cerebrospinal fluid*


  • ATP Binding Cassette Transporter, Subfamily B
  • Pharmaceutical Preparations