Structure-Brain Exposure Relationships in Rat and Human Using a Novel Data Set of Unbound Drug Concentrations in Brain Interstitial and Cerebrospinal Fluids

New experimental methodologies were applied to measure the unbound brain-to-plasma concentration ratio (K-p,K-uu,K-brain) and the unbound CSF-to-plasma concentration ratio (K-p,K-uu,K-CSF) in rats for 43 structurally diverse drugs. The relationship between chemical structure and K-p,K-uu,K-brain was dominated by hydrogen bonding. Contrary to popular understanding based on the total brain-to-plasma concentration ratio (logBB), lipophilicity was not a determinant of unbound brain exposure. Although changing the number of hydrogen bond acceptors is a useful design strategy for optimizing K-p,K-uu,K-brain, future improvement of in silico prediction models is dependent on the accommodation of active drug transport. The structure-brain exposure relationships found in the rat also hold for humans, since the rank order of the drugs was similar for human and rat K-p,K-uu,K-CSF. This cross-species comparison was supported by K-p,K-uu,K-CSF being within 3-fold of K-p,K-uu,K-brain in the rat for 33 of 39 drugs. It was, however, also observed that K-p,K-uu,K-CSF overpredicts K-p,K-uu,K-brain for highly effluxed drugs, indicating lower efflux capacity of the blood-cerebrospinal fluid barrier compared to the blood-brain barrier.