title: Structure-brain exposure relationships in rat and human using a novel data set of unbound drug concentrations in brain interstitial and cerebrospinal fluids.
abstract: New experimental methodologies were applied to measure the unbound brain-to-plasma concentration ratio (K(p,uu,brain)) and the unbound CSF-to-plasma concentration ratio (K(p,uu,CSF)) in rats for 43 structurally diverse drugs. The relationship between chemical structure and K(p,uu,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,uu,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,uu,CSF). This cross-species comparison was supported by K(p,uu,CSF) being within 3-fold of K(p,uu,brain) in the rat for 33 of 39 drugs. It was, however, also observed that K(p,uu,CSF) overpredicts K(p,uu,brain) for highly effluxed drugs, indicating lower efflux capacity of the blood-cerebrospinal fluid barrier compared to the blood-brain barrier.
authors.affiliation: Discovery DMPK, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden. Markus.Friden@farmbio.uu.se
authors.forename: Markus
authors.initials: M
authors.lastname: Fridén
authors.forename: Susanne
authors.initials: S
authors.lastname: Winiwarter
authors.forename: Gunilla
authors.initials: G
authors.lastname: Jerndal
authors.forename: Ola
authors.initials: O
authors.lastname: Bengtsson
authors.forename: Hong
authors.initials: H
authors.lastname: Wan
authors.forename: Ulf
authors.initials: U
authors.lastname: Bredberg
authors.forename: Margareta
authors.initials: M
authors.lastname: Hammarlund-Udenaes
authors.forename: Madeleine
authors.initials: M
authors.lastname: Antonsson
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism*; D006801:Humans; D016014:Linear Models; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000134:cerebrospinal fluid* / Q000737:chemistry* / Q000378:metabolism; D010599:Pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004364:Pharmaceutical Preparations