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P-glycoprotein (P-gp, ABCB1) is a highly efficient drug efflux pump expressed in brain, liver, and small intestine, but also in tumor cells, that affects pharmacokinetics and confers therapy resistance for many anticancer drugs. The aim of this study was to investigate the impact of P-gp on tamoxifen and its primary active metabolites, 4-hydroxytamoxifen, N-desmethyltamoxifen, and endoxifen. We used in vitro transport assays and Abcb1a/1b(Ϫ/Ϫ) mice to investigate the impact of P-gp on the oral availability and brain penetration of tamoxifen and its metabolites. Systemic exposure of tamoxifen and its metabolites after oral administration of tamoxifen (50 mg/kg) was not changed in the absence of P-gp. However, brain accumulation of tamoxifen, 4-hydroxytamoxifen, and N-desmethyltamoxifen were modestly, but significantly (1.5-to 2-fold), increased. Endoxifen, however, displayed a 9-fold higher brain penetration at 4 h after administration. Endoxifen was transported by P-gp in vitro. Upon direct oral administration of endoxifen (20 mg/kg), systemic exposure was slightly decreased in Abcb1a/1b(Ϫ/Ϫ) mice, but brain accumulation of endoxifen was dramatically increased (up to 23-fold at 4 h after administration). Shortly after high-dose intravenous administration (5 or 20 mg/kg), endoxifen brain accumulation was increased only 2-fold in Abcb1a/1b(Ϫ/Ϫ) mice compared with wild-type mice, suggesting a partial saturation of P-gp at the blood-brain barrier. Endoxifen, the clinically most relevant metabolite of tamoxifen, is a P-gp substrate in vitro and in vivo, where P-gp limits its brain penetration. P-gp might thus be relevant for tamoxifen/endoxifen resistance of P-gp-positive breast cancer and tumors positioned behind a functional blood-brain barrier.

ABSTRACT:The second-generation tyrosine kinase inhibitor and anticancer drug axitinib is a potent, orally active inhibitor of the vascular endothelial growth factor receptors 1, 2, and 3. Axitinib has clinical activity against solid tumors such as metastatic renal cell carcinoma and advanced pancreatic cancer. We studied axitinib transport using Madin-Darby canine kidney II cells overexpressing human ABCB1 or ABCG2 or murine Abcg2. Axitinib was a good substrate of ABCB1 and Abcg2, whereas transport activity by ABCG2 was moderate. These transporters may therefore contribute to axitinib resistance in tumor cells. Upon oral administration of axitinib, Abcg2(؊/؊) and Abcb1a/1b;Abcg2(؊/؊) mice displayed 1.7-and 1.8-fold increased axitinib areas under the plasma concentration-time curve from 0 to 4 compared with those of wild-type mice. Plasma concentrations in Abcb1a/1b(؊/؊) mice were not significantly increased. In contrast, relative brain accumulation of axitinib in Abcb1a/1b(؊/؊) and Abcb1a/1b;Abcg2(؊/؊) mice was, respectively, 6.8-and 13.9-fold higher than that in wild-type mice at 1 h and 4.9-and 20.7-fold at 4 h after axitinib administration. In Abcg2(؊/؊) mice, we found no significant differences in brain accumulation compared with those in wild-type mice. Thus, Abcb1 strongly restricts axitinib brain accumulation and completely compensates for the loss of Abcg2 at the blood-brain barrier, whereas Abcg2 can only partially take over Abcb1-mediated axitinib efflux. Hence, Abcg2 has a stronger impact on axitinib oral plasma pharmacokinetics, whereas Abcb1 is the more important transporter at the blood-brain barrier. These findings illustrate that in vitro transport data for ABCB1 and ABCG2 cannot always be simply extrapolated to the prediction of the relative impact of these transporters on oral availability versus brain penetration. IntroductionThe ATP-binding cassette (ABC) transporters P-glycoprotein (Pgp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) affect the disposition of a variety of endogenous and exogenous compounds, including many anticancer drugs. Both transporters are expressed at the apical membranes of enterocytes, hepatocytes, and renal tubular epithelial cells, where they potentially limit gastrointestinal absorption or mediate direct intestinal, hepatic, or renal excretion of their substrates. Moreover, ABCB1-and ABCG2-mediated efflux activity in brain endothelial capillary cells of the blood-brain barrier (BBB) is crucial for the protection of the central nervous system from harmful compounds (Schinkel and Jonker, 2003;Vlaming et al., 2009). In addition, ABC transporters are expressed in many tumor types, mediating multidrug resistance against anticancer drugs (Borst and Oude Elferink, 2002).Only recently, the combined role of ABCB1 and ABCG2 at the BBB in limiting brain accumulation of shared substrates has been studied in detail using Abcb1a/1b;Abcg2(Ϫ/Ϫ) combination knockout mice. It was found that brain penetration of topotecan and several tyrosine kinase inhibitors (TKIs) includ...