Abstract
ATP-binding cassette transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) have been shown to work in concert to restrict brain penetration of several tyrosine kinase inhibitors. It has been reported that P-gp is dominant in limiting transport of many dual P-gp/BCRP substrates across the blood-brain barrier (BBB). This study investigated the influence of P-gp and BCRP on the central nervous system (CNS) penetration of sorafenib, a multitargeted tyrosine kinase inhibitor currently being evaluated in clinical trials for glioma. In vitro studies showed that BCRP has a high affinity for sorafenib. Sorafenib inhibited P-gp, but did not seem to be a P-gp substrate in vitro. CNS distribution studies showed that transport of sorafenib to the brain was restricted because of active efflux at the BBB. The brain-to-plasma equilibrium-distribution coefficient (area under the concentration-time profiles for plasma/area under the concentration-time profiles for brain) was 0.06 in wild-type mice. Steady-state brain-to-plasma concentration ratio of sorafenib was approximately 0.36 ± 0.056 in the Bcrp1(−/−) mice, 0.11 ± 0.021 in the Mdr1a/b(−/−) mice, and 0.91 ± 0.29 in the Mdr1a/b(−/−)Bcrp1(−/−) mice compared with 0.094 ± 0.007 in the wild-type mice. Sorafenib brain-to-plasma ratios increased on coadministration of the dual P-gp/BCRP inhibitor elacridar such that the ratio in wild-type mice (0.76 ± 0.24), Bcrp1(−/−) mice (1.03 ± 0.33), Mdr1a/b(−/−) mice (1.3 ± 0.29), and Mdr1a/b(−/−)Bcrp1(−/−) mice (0.73 ± 0.35) were not significantly different. This study shows that BCRP and P-gp together restrict the brain distribution of sorafenib with BCRP playing a dominant role in the efflux of sorafenib at the BBB. These findings are clinically relevant to chemotherapy in glioma if restricted drug delivery to the invasive tumor cells results in decreased efficacy.
Footnotes
This work was supported by the National Institutes of Health National Cancer Institute [Grant CA138437] (to W.F.E., J.R.O.) and a grant from the Children's Cancer Research Fund at the University of Minnesota (to W.F.E., J.R.O.). Financial support for S.A. was provided by a Doctoral Dissertation Fellowship from the University of Minnesota, a Edward G. Rippie Fellowship, and a Ronald J. Sawchuk Fellowship in Pharmacokinetics from the Department of Pharmaceutics at the University of Minnesota.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.175034.
-
ABBREVIATIONS:
- ABC
- ATP-binding cassette
- CNS
- central nervous system
- BBB
- blood-brain barrier
- MDR1
- multidrug resistance protein 1
- P-gp
- P-glycoprotein
- BCRP
- breast cancer resistance protein
- TKI
- tyrosine kinase inhibitor
- A-to-B
- apical-to-basolateral
- B-to-A
- basolateral-to-apical
- B/P
- brain-to-plasma
- Mdr1
- gene encoding the murine P-glycoprotein
- MDR1
- gene encoding the human P-glycoprotein
- Bcrp1
- gene encoding the murine breast cancer resistance protein
- MS
- mass spectrometry
- LC
- liquid chromatography
- AG1478
- tyrphostin
- MDCKII
- Madin-Darby canine kidney II
- GF120918 (elacridar)
- N-[4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]-5-methoxy-9-oxo-10H-acridine-4-carboxamide]
- LY335979 (zosuquidar)
- (R)-4-((1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo-(a,e)cyclopropa(c)cycloheptan-6-yl)-α-((5-quinoloyloxy)methyl)-1-piperazine ethanol, trihydrochloride
- 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
- FVB
- Friend leukemia virus strain B
- DMSO
- dimethyl sulfoxide
- AUC
- area under the curve.
- Received September 9, 2010.
- Accepted October 14, 2010.
- Copyright © 2011 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.
|