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Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)gene dosage on plasma pharmacokinetics and brain accumulation of dasatinib, sorafenib and sunitinib.


J Pharmacol Exp Ther. 2013 Jul 10;


Authors: Tang SC, de Vries N, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH


Abstract

Low brain accumulation of anticancer drugs due to efflux transporters may limit chemotherapeutic efficacy, necessitating better understanding of the underlying mechanisms. P-glycoprotein (Abcb1a/1b) and breast cancer resistance protein (Abcg2) combination knockout mice often display disproportionately increased brain accumulation of shared drug substrates compared to single transporter knockout mice. Recently developed pharmacokinetic models could explain this phenomenon. To experimentally test these models and their wider relevance for tyrosine kinase inhibitors (TKIs) and other drugs, we selected dasatinib, sorafenib and sunitinib because of their divergent oral availability and brain accumulation profiles: brain accumulation of dasatinib is mainly restricted by Abcb1, that of sorafenib mainly by Abcg2, and that of sunitinib equally by Abcb1 and Abcg2. We analyzed the effect of halving the efflux activity of these transporters at the blood-brain barrier (BBB) by generating heterozygous Abcb1a/1b;Abcg2 knockout mice, and testing plasma and brain levels of the drugs after oral administration at 10 mg/kg. RT-PCR analysis confirmed ~2-fold decreased expression of both transporters in brain. Interestingly, whereas complete knockout of the transporters caused 24- to 36-fold increases in brain accumulation of the drugs, the heterozygous mice only displayed 1.6- to 1.9-fold increases of brain accumulation relative to wild-type mice. These results are well in line with the predictions of the pharmacokinetic models, and provide strong support for their validity for a wider range of drugs. Moreover, retrospective analysis of fetal accumulation of drugs across the placenta in Abcb1a/1b heterozygous knockout pups suggests that these models equally apply to the maternal-fetal barrier.

PMID: 23843632 [PubMed - as supplied by publisher]