RGD Reference Report - Use of cassette dosing approach to examine the effects of P-glycoprotein on the brain and cerebrospinal fluid concentrations in wild-type and P-glycoprotein knockout rats. - Rat Genome Database

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Use of cassette dosing approach to examine the effects of P-glycoprotein on the brain and cerebrospinal fluid concentrations in wild-type and P-glycoprotein knockout rats.

Authors: Liu, Xingrong  Cheong, Jonathan  Ding, Xiao  Deshmukh, Gauri 
Citation: Liu X, etal., Drug Metab Dispos. 2014 Apr;42(4):482-91. doi: 10.1124/dmd.113.055590. Epub 2014 Jan 7.
RGD ID: 150429695
Pubmed: PMID:24398459   (View Abstract at PubMed)
DOI: DOI:10.1124/dmd.113.055590   (Journal Full-text)

The study objectives were 1) to test the hypothesis that the lack of P-glycoprotein (P-gp) and the inhibition of breast cancer resistance protein (Bcrp) at the blood-brain barrier after cassette dosing of potent P-gp and Bcrp inhibitors were due to low plasma concentrations of those inhibitors and 2) to examine the effects of P-gp on the unbound brain (C(u,brain)) and cerebrospinal fluid (CSF) concentrations (C(u,CSF)) of P-gp substrates in rats. In vitro inhibition of 11 compounds (amprenavir, citalopram, digoxin, elacridar, imatinib, Ko143 [(3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1',2':1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester], loperamide, prazosin, quinidine, sulfasalazine, and verapamil) on P-gp and Bcrp was examined in P-gp- and Bcrp-expressing Madin-Darby canine kidney cells, respectively. An in vivo study was conducted in wild-type and Mdr1a(-/-) rats after subcutaneous cassette dosing of the 11 compounds at 1-3 mg/kg, and the brain, CSF, and plasma concentrations of these compounds were determined. At the maximal unbound concentrations observed in rats at 1-3 mg/kg, P-gp and Bcrp were not inhibited by a cassette of the 11 compounds. For non-P-gp/Bcrp substrates, similar C(u,brain), C(u,CSF), and unbound plasma concentrations (C(u,plasma)) were observed in wild-type and P-gp knockout rats. For P-gp/Bcrp substrates, C(u,brain) <= C(u,CSF) <= C(u,plasma) in wild-type rats, but C(u,brain) and C(u,CSF) increased in the P-gp knockout rats and were within 3-fold of C(u,plasma) for six of the seven P-gp substrates. These results indicate that P-gp and Bcrp inhibition at the blood-brain barrier is unlikely in cassette dosing and also suggest that P-gp and Bcrp activity at the blood-CSF barrier is functionally not important in determination of the CSF concentration for their substrates.



Phenotype Annotations    

Mammalian Phenotype
Objects Annotated

Genes (Rattus norvegicus)
Abcb1a  (ATP binding cassette subfamily B member 1A)
Abcb1aem1Sage  (ATP binding cassette subfamily B member 1A; ZFN induced mutant 1, Sage)

Strains
SD-Abcb1aem1Sage -/-  (SD-Abcb1aem1-/Abcb1aem1-)


Additional Information