title: Quantitative evaluation of the impact of active efflux by p-glycoprotein and breast cancer resistance protein at the blood-brain barrier on the predictability of the unbound concentrations of drugs in the brain using cerebrospinal fluid concentration as a surrogate.
abstract: This study investigated the impact of the active efflux mediated by P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) at the blood-brain barrier (BBB) on the predictability of the unbound brain concentration (C(u,brain)) by the concentration in the cerebrospinal fluid (CSF) (C(u,CSF)) in rats. C(u,brain) is obtained as the product of the total brain concentration and unbound fraction in the brain (f(u,brain)) determined in vitro in brain slices. Twenty-five compounds, including P-gp and/or Bcrp substrates, were given a constant intravenous infusion, and their plasma, brain, and CSF concentrations were determined. P-gp and/or Bcrp substrates, such as verapamil, loperamide, flavopiridol, genistein, quinidine, dantrolene, daidzein, cimetidine, and pefloxacin, showed a higher CSF-to-brain unbound concentration ratio (K(p,uu,CSF/brain)) compared with non-P-gp and non-Bcrp substrates. K(p,uu,CSF/brain) values of P-gp-specific (quinidine and verapamil) and Bcrp-specific (daidzein and genistein) substrates were significantly decreased in Mdr1a/1b(-/-) and Bcrp(-/-) mice, respectively. Furthermore, consistent with the contribution of P-gp and Bcrp to the net efflux at the BBB, K(p,uu,CSF/brain) values of the common substrates (flavopiridol and erlotinib) were markedly decreased in Mdr1a/1b(-/-)/Bcrp(-/-) mice, but only moderately or weakly in Mdr1a/1b(-/-) mice and negligibly in Bcrp(-/-) mice. In conclusion, predictability of C(u,brain) by C(u,CSF) decreases along with the net transport activities by P-gp and Bcrp at the BBB. C(u,CSF) of non-P-gp and non-Bcrp substrates can be a reliable surrogate of C(u,brain) for lipophilic compounds.
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kodaira
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Takuya
authors.initials: T
authors.lastname: Fujita
authors.forename: Junko
authors.initials: J
authors.lastname: Ushiki
authors.forename: Eiichi
authors.initials: E
authors.lastname: Fuse
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000493:pharmacokinetics; D001693:Biological Transport, Active; D015415:Biomarkers; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004285:Dogs; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000378:metabolism*; D011485:Protein Binding; D011799:Quinazolines / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000493:pharmacokinetics; D011802:Quinidine / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats
chemical_list: C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D015415:Biomarkers; D009363:Neoplasm Proteins; D011799:Quinazolines; C095122:multidrug resistance protein 3; D000069347:Erlotinib Hydrochloride; D011802:Quinidine