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Abcc4 together with Abcb1 and Abcg2 form a robust co-operative drug efflux system that restricts the brain entry of camptothecin analogs.


Clin Cancer Res. 2013 Mar 5;


Authors: Lin F, Marchetti S, Pluim D, Iusuf D, Mazzanti R, Schellens JH, Beijnen JH, van Tellingen O


Abstract

PURPOSE: Multidrug resistance-associated protein 4 (ABCC4) shares many features with P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), including broad substrate affinity and expression at the blood-brain barrier (BBB). However, the pharmacological relevance of ABCC4 at the BBB is difficult to evaluate since most drugs are also substrates of ABCB1 and/or ABCG2. EXPERIMENTAL DESIGN: We have created a mouse strain in which all these alleles are inactivated to assess their impact on brain delivery of camptothecin analogs, an important class of antineoplastic agents and substrates of these transporters. Wild-type (WT), Abcg2-/-, Abcb1a/b-/-, Abcc4-/-, Abcb1a/b;Abcg2-/-, Abcg2;Abcc4-/- and Abcb1a/b;Abcg2;Abcc4-/- mice received i.v. topotecan, irinotecan, SN-38 or gimatecan alone or with concomitant oral elacridar. Drug levels were analyzed by HPLC. RESULTS: We found that additional deficiency of Abcc4 in Abcb1a/b;Abcg2-/- mice significantly increased the brain concentration of all camptothecin analogs by 1.2-fold (gimatecan) to 5.8-fold (SN-38). The presence of Abcb1a/b or Abcc4 alone was sufficient to reduce the brain concentration of SN38 to the level in WT mice. Strikingly, the brain distribution of gimatecan in brain of WT mice was more than 220-fold and 40-fold higher than that of SN-38 and topotecan, respectively. CONCLUSION: Abcc4 limits the brain penetration of camptothecin analogs and teams up with Abcb1a/b and Abcg2 to form a robust cooperative drug-efflux system. This concerted action limits the usefulness of selective ABC-transport inhibitors to enhance drug entry for treatment of intracranial diseases. Our results also suggest that gimatecan might be a better candidate than irinotecan for clinical evaluation against intracranial tumors.

PMID: 23461902 [PubMed - as supplied by publisher]