title: Differential role of P-glycoprotein and breast cancer resistance protein in drug distribution into brain, CSF and peripheral nerve tissues in rats.
abstract: 1. This study was designed to evaluate how the absence of P-glycoprotein (Pgp, Mdr1a), breast cancer-resistance protein (Bcrp, Abcg2) or both affects drug distribution into sciatic nerves, brain and cerebrospinal fluid (CSF) in rats. 2. Pgp substrate (loperamide), BCRP substrates (dantrolene and proprietary compound X) and dual substrates (imatinib and proprietary compound Y) were well distributed into sciatic nerves with comparable nerve to plasma concentration ratios between wild-type and knockout (KO) rats. 3. Brain exposure increased substantially in Mdr1a(-/-) rats for loperamide and in Mdr1a(-/-)/Abcg2(-/-) rats for imatinib and compound Y, but minimally to modestly in Abcg2(-/-) rats for dantrolene and compound X. The deletion of Mdr1a or Abcg2 alone had little effect on brain distribution of compound Y. 4. While CSF to unbound brain concentration ratio remained ≥3 in the KO animals for dantrolene, compounds X and Y, it was reduced to 1 in the Mdr1a(-/-)/Abcg2(-/-) rats for imatinib. 5. The data indicate that Pgp and Bcrp do not play significant roles in drug distribution into peripheral nerve tissues in rats, while working in concert to regulate brain penetration. Our results further support that CSF concentration may not be a good surrogate for unbound brain concentration of efflux substrates.
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen Inc , Cambridge, MA , USA.
authors.forename: Liyue
authors.initials: L
authors.lastname: Huang
authors.forename: Xingwen
authors.initials: X
authors.lastname: Li
authors.forename: Jonathan
authors.initials: J
authors.lastname: Roberts
authors.forename: Brett
authors.initials: B
authors.lastname: Janosky
authors.forename: Min-Hwa Jasmine
authors.initials: MH
authors.lastname: Lin
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003620:Dantrolene / Q000493:pharmacokinetics* / Q000494:pharmacology; D008139:Loperamide / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012584:Sciatic Nerve / Q000378:metabolism*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D008139:Loperamide; C095122:multidrug resistance protein 3; D003620:Dantrolene
keywords: ABC transporters; blood CSF barrier; blood–brain barrier; efflux; knockout rat; tissue distribution