Utility of Cerebrospinal Fluid Drug Concentration as a Surrogate for Unbound Brain Concentration in Nonhuman Primates

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,C- 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,C- 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,K- uu,K- ISF) and CSF-to-plasma unbound concentration ratios (K-p,K- uu,K- CSF) that were appreciably lower than unity. Although the K-p,K- uu,K- CSF of quinidine, verapamil, and desloratadine showed a trend of overestimating the K-p,K- uu,K- ISF, K-p,K- uu,K- CSF showed a good agreement with K-p,K- uu,K- ISF within 3-fold variations for all compounds examined. C-u,C- 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.