Cerebrospinal Fluid Can Be Used as a Surrogate to Assess Brain Exposures of Breast Cancer Resistance Protein and P-Glycoprotein Substrates

Gao, Xiao; Black, Cheryl; Hetu, Gregg; Sands, Eric; Wang, Joy; Caputo, Robin; Rohde, Ellen; Gan, Liang‐Shang

doi:10.1124/dmd.111.043703

Cited by 30 publications

(34 citation statements)

References 25 publications

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“…Our studies have strong implications for using CSF as a surrogate for brain exposure following systemic administration of BCRP and P-gp substrates (Xiao et al, 2012). For P-gp substrates, conventional knowledge posits that CSF drug concentration is only influenced by BBB and CP P-gp (Kodaira et al, 2011).…”

Section: Discussionmentioning

confidence: 87%

Drug Transporters on Arachnoid Barrier Cells Contribute to the Blood–Cerebrospinal Fluid Barrier

et al. 2013

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The subarachnoid space, where cerebrospinal fluid (CSF) flows over the brain and spinal cord, is lined on one side by arachnoid barrier (AB) cells that form part of the blood-CSF barrier. However, despite the fact that drugs are administered into the CSF and CSF drug concentrations are used as a surrogate for brain drug concentration following systemic drug administration, the tightjunctioned AB cells have never been examined for whether they express drug transporters that would influence CSF and central nervous system drug disposition. Hence, we characterized drug transporter expression and function in AB cells. Immunohistochemical analysis showed P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in mouse AB cells but not other meningeal tissue. The Gene Expression Nervous System Atlas (GENSAT) database and the Allen Mouse Brain Atlas confirmed these observations. Microarray analysis of mouse and human arachnoidal tissue revealed expression of many drug transporters and some drug-metabolizing enzymes. Immortalized mouse AB cells express functional P-gp on the apical (dura-facing) membrane and BCRP on both apical and basal (CSF-facing) membranes. Thus, like blood-brain barrier cells and choroid plexus cells, AB cells highly express drug transport proteins and likely contribute to the blood-CSF drug permeation barrier.

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Section: Discussionmentioning

confidence: 87%

Drug Transporters on Arachnoid Barrier Cells Contribute to the Blood–Cerebrospinal Fluid Barrier

et al. 2013

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“…1). WEB 2086 did not relevantly inhibit BCRP transport, and dantrolene was reported not to inhibit P-gp activity represented by digoxin transcellular transport across CaCo-2 monolayer (Xiao et al, 2012), suggesting no mutual inhibition after coinfusion of both WEB 2086 and dantrolene.…”

Section: Resultsmentioning

confidence: 92%

“…Plasma and brain concentration data are given in Supplemental Table 1. WEB 2086 was selected as a P-gp substrate because its P-gp-dependent brain penetration has already been demonstrated in vivo using Mdr1a knockout mice (Leusch et al, 2002). Dantrolene was chosen as a BCRP substrate because, in contrast to the majority of BCRP substrates, it is not or is only a weak substrate for P-gp in vitro and in vivo (Enokizono et al, 2008;Kodaira et al, 2010;Xiao et al, 2012). The BPRs of WEB 2086 were calculated on the basis of total [ 14 C]WEB 2086-derived radioactivity.…”

Section: Resultsmentioning

confidence: 99%

“…As a P-gp substrate, the compound WEB 2086 (Leusch et al, 2002). Dantrolene was selected as a specific BCRP substrate based on data from in vitro and in vivo literature (Enokizono et al, 2008;Kodaira et al, 2010;Xiao et al, 2012). Both [ 14 C]WEB 2086 and dantrolene are known to exhibit a short mean residence time (MRT) in rats: MRT of WEB 2086 is 0.44 hour (V. Haeselbarth, G. Schoenfels, and H. Foerster, unpublished data), and MRT of dantrolene was reported to be 0.52 hour by Meyler et al (1979) and 3.1 hours by Karan et al (1996).…”

Section: Introductionmentioning

confidence: 99%

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Brain Penetration of WEB 2086 (Apafant) and Dantrolene in Mdr1a (P-Glycoprotein) and Bcrp Knockout Rats

et al. 2014

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Transporter gene knockout rat models are attracting increasing interest for mechanistic studies of new drugs as transporter substrates or inhibitors in vivo. However, limited data are available on the functional validity of such models at the blood-brain barrier. Therefore, the present study evaluated Mdr1a [P-glycoprotein (P-gp)], Bcrp, and combined Mdr1a/Bcrp knockout rat strains for the influence of P-gp and breast cancer resistance protein (BCRP) transport proteins on brain penetration of the selective test substrates [ .5-fold in double Mdr1a/Bcrp knockouts, and 7.3-fold in zosuquidar-treated wild-type rats, but was unchanged in Bcrp knockout rats. Mean BPR of dantrolene increased 3.3-fold in Bcrp knockouts and 3.9-fold in double Mdr1a/Bcrp knockouts compared with wild type, but was unchanged in the Mdr1a knockouts. The human intestinal CaCo-2 cell bidirectional transport system in vitro confirmed the in vivo finding that [ 14 C]WEB 2086 is a substrate of P-gp but not of BCRP. Therefore, Mdr1a, Bcrp, and combined Mdr1a/Bcrp knockout rats provide functional absence of these efflux transporters at the blood-brain barrier and are a suitable model for mechanistic studies on the brain penetration of drug candidates.

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“…Many studies have utilized global transporter knockout (KO) animal models and analyzed the CSF as a surrogate for the amount of unbound drug available to the brain [39][40][41][42]. However, this approach does not address the question of how much each barrier contributes to the distribution of a drug within the CNS.…”

Section: Animal Models Used To Study Drug Concentrations In the Cnsmentioning

confidence: 99%

Characterization of Cre Mouse Models to Target CNS Barriers for Generating Conditional Knockouts of ABC Transporters

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Cerebrospinal Fluid Can Be Used as a Surrogate to Assess Brain Exposures of Breast Cancer Resistance Protein and P-Glycoprotein Substrates

Abstract: ABSTRACT:The objectives of the study were to characterize the selectivity of dantrolene to breast cancer resistance protein (Bcrp) and to evaluate whether cerebrospinal fluid (CSF) can be used as a surrogate to assess brain exposures of BCRP and P-glycoprotein (

Cited by 30 publications

References 25 publications

Drug Transporters on Arachnoid Barrier Cells Contribute to the Blood–Cerebrospinal Fluid Barrier

Drug Transporters on Arachnoid Barrier Cells Contribute to the Blood–Cerebrospinal Fluid Barrier

Brain Penetration of WEB 2086 (Apafant) and Dantrolene in Mdr1a (P-Glycoprotein) and Bcrp Knockout Rats

Characterization of Cre Mouse Models to Target CNS Barriers for Generating Conditional Knockouts of ABC Transporters

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