Abstract
A synergistic effect of P-glycoprotein (P-gp)/Abcb1a and breast cancer resistance protein (Bcrp)/Abcg2 was reported to limit the brain penetration of their common substrates. This study investigated this based on pharmacokinetics using Mdr1a/1b(−/−), Bcrp(−/−), and Mdr1a/1b(−/−)/Bcrp(−/−) mice. Comparison of the brain- and testis-to-plasma ratios (Cbrain/Cplasma and Ctestis/Cplasma, respectively) of the reference compounds quinidine and dantrolene for P-gp and Bcrp, respectively, indicates that impairment of either P-gp and Bcrp did not cause any change in the efflux activities of Bcrp or P-gp, respectively, at both the blood-brain barrier (BBB) and blood-testis barrier (BTB). The Cbrain/Cplasma and Ctestis/Cplasma of the common substrates erlotinib, flavopiridol, and mitoxantrone were markedly increased in Mdr1a/1b(−/−)/Bcrp(−/−) mice even compared with Mdr1a/1b(−/−) and Bcrp(−/−) mice. Efflux activities by P-gp and Bcrp relative to passive diffusion at the BBB and BTB were separately evaluated based on the Cbrain/Cplasma and Ctestis/Cplasma in the knockout strains to the wild-type strain. P-gp made a larger contribution than Bcrp to the net efflux of the common substrates, but Bcrp activities were also significantly larger than passive diffusion. These parameters could reasonably account for the marked increase in Cbrain/Cplasma and Ctestis/Cplasma in the Mdr1a/1b(−/−)/Bcrp(−/−) mice. In conclusion, the synergistic effect of P-gp and Bcrp on Cbrain/Cplasma and Ctestis/Cplasma can be explained by their contribution to the net efflux at the BBB and BTB without any interaction between P-gp and Bcrp.
Footnotes
This work was supported in part by the Ministry of Education, Culture, Sports, Science, and Technology [Grants 20249008, 20390046] (to Y.S. and H.K., respectively) and by the Kanal Foundation for the Promotion of Medical Science grant.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.162321.
-
ABBREVIATIONS:
- P-gp
- P-glycoprotein
- Mdr
- multidrug resistance protein
- Bcrp
- breast cancer resistance protein
- BBB
- blood-brain barrier
- BTB
- blood-testis barrier
- ABC
- ATP binding cassette
- MDCK
- Madin-Darby canine kidney
- GFP
- green fluorescent protein
- L-Mdr1a
- LLC-PK1 cells expressing mouse Mdr1a
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- CFR
- corrected flux ratio
- PS
- permeability surface area
- Cbrain/Cplasma
- brain-to-plasma ratio
- Ctestis/Cplasma
- testis-to-plasma ratio
- MRP
- multidrug resistance-associated protein
- GF120918
- N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide
- HMR-1275
- (−)cis-5,7-dihydroxy-2-(2-chlorophenyl)-8-(4R-(3S-hydroxy-1-methyl) piperidinyl)-4H-1-benzopyran-4-one.
- Received October 5, 2009.
- Accepted March 15, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|