An inhibitor of MRP-1 and BCRP
Elacridar is an inhibitor of breast cancer resistance protein (BCRP) and P-glycoprotein (P-GP) that has been used to improve the brain distribution of drugs. Recent studies have revealed that elacridar could probably be the substrate of these multidrug transporters (MDTs) [2].
Recent studies had shown that elacridar and taxanes co-administrated orally could increase plasma concentrations of docetaxel (four-fold) and paclitaxel (10.7-fold) in mice. Co-administration of elacridar with taxanes and ritonavir could lead to a further increase in plasma concentrations of docetaxel (37.4-fold) and paclitaxel (31.9-fold). Besides, co-administration of elacridar with taxanes and ritonavir could potently increase taxanes concentration in the brain, but not increase the brain penetration of the taxanes [1].
Elacridar co-administrated orally with crizotinib has shown to increase the crizotinib concentrations in plasma and brain as well as increase the brain-to-plasma ratios of crizotinib, indicating that co-administration of crizotinib with elacridar could increase oral availability of crizotinib and delivery of crizotinib to the brain [2].
Apart from these, the uptake of elacridar at nanomolar doses in mouse brain was proved to be limited by Pgp- and Bcrp1-induced efflux at the blood - brain barrier. In vitro, Elacridar was indicated a low intracellular accumulation at nanomolar concentrations and a high intracellular accumulation at micromolar concentrations in Pgp- and Bcrp1-overexpressing cell lines [3].
参考文献:
1.Hendrikx JJ1, Lagas JS2, Wagenaar E3, Rosing H2, Schellens JH4, Beijnen JH5, Schinkel AH3. Oral co-administration of elacridar and ritonavir enhances plasma levels of oral paclitaxel and docetaxel without affecting relative brain accumulation. Br J Cancer. 2014 May 27;110(11):2669-76. doi: 10.1038/bjc.2014.222. Epub 2014 Apr 29.
2.Chuan Tang S1, Nguyen LN, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH.Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Int J Cancer. 2014 Mar 15;134(6):1484-94. doi: 10.1002/ijc.28475. Epub 2013 Oct 3.
3.Bankstahl JP1, Bankstahl M, R?mermann K, Wanek T, Stanek J, Windhorst AD, Fedrowitz M, Erker T, Müller M, L?scher W, Langer O, Kuntner C.Tariquidar and elacridar are dose-dependently transported by P-glycoprotein and Bcrp at the blood-brain barrier: a small-animal positron emission tomography and in vitro study. Drug Metab Dispos. 2013 Apr;41(4):754-62. doi: 10.1124/dmd.112.049148. Epub 2013 Jan 10.
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