title: Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) gene dosage on plasma pharmacokinetics and brain accumulation of dasatinib, sorafenib, and sunitinib.
abstract: Low brain accumulation of anticancer drugs due to efflux transporters may limit chemotherapeutic efficacy, necessitating a 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 with 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 and other drugs, we selected dasatinib, sorafenib, and sunitinib because of their divergent oral availability and brain accumulation profiles: the 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 by generating heterozygous Abcb1a/1b;Abcg2 knockout mice and testing the plasma and brain levels of the drugs after oral administration at 10 mg/kg. Real-time reverse transcription-polymerase chain reaction analysis confirmed the ∼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.
authors.affiliation: Division of Molecular Oncology, the Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Seng Chuan
authors.initials: SC
authors.lastname: Tang
authors.forename: Niels
authors.initials: N
authors.lastname: de Vries
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Sparidans
authors.forename: Els
authors.initials: E
authors.lastname: Wagenaar
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics* / Q000502:physiology*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D000069439:Dasatinib; D005260:Female; D018628:Gene Dosage; D006207:Half-Life; D007211:Indoles / Q000493:pharmacokinetics*; D008297:Male; D008431:Maternal-Fetal Exchange; D051379:Mice; D018345:Mice, Knockout; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010671:Phenylurea Compounds / Q000493:pharmacokinetics*; D011247:Pregnancy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000493:pharmacokinetics*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012727:Sex Characteristics; D000077157:Sorafenib; D000077210:Sunitinib; D013844:Thiazoles / Q000493:pharmacokinetics*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D018076:DNA, Complementary; D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D013844:Thiazoles; D009536:Niacinamide; D012313:RNA; C095122:multidrug resistance protein 3; D000077157:Sorafenib; D011505:Protein-Tyrosine Kinases; D000069439:Dasatinib; D000077210:Sunitinib