RT Journal Article SR Electronic T1 An Unexpected Synergist Role of P-Glycoprotein and Breast Cancer Resistance Protein on the Central Nervous System Penetration of the Tyrosine Kinase Inhibitor Lapatinib (N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016) JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 439 OP 442 DO 10.1124/dmd.108.024646 VO 37 IS 2 A1 Joseph W. Polli A1 Katie L. Olson A1 John P. Chism A1 Lisa St. John-Williams A1 Russell L. Yeager A1 Sesha M. Woodard A1 Vicky Otto A1 Stephen Castellino A1 Victoria E. Demby YR 2009 UL http://dmd.aspetjournals.org/content/37/2/439.abstract AB Lapatinib is a tyrosine kinase inhibitor approved for use in combination with capecitabine to treat advanced or metastatic breast cancers overexpressing human epidermal receptor 2 (ErbB2). This work investigated the role of P-glycoprotein (Pgp; the protein from the Mdr1a/b gene) and breast cancer resistance protein (Bcrp; the protein from the Bcrp1 gene) in modulating the central nervous system penetration of lapatinib at steady-state conditions in FVBn mice (wild-type), Mdr1a/b(–/–), Bcrp1(–/–), and Mdr1a/b(–/–)/Bcrp1(–/–) knockout mice. After an intravenous infusion of lapatinib for 24 h to a targeted steady-state plasma concentration of 700 ng/ml (0.3 mg/kg/h) or 7000 ng/ml (3 mg/kg/h), lapatinib brain-to-plasma ratios were approximately 3- to 4-fold higher in Mdr1a/b(–/–) knockout mice (ratio range from 0.09 to 0.16) compared with wild-type mice (ratio range from 0.03 to 0.04). There was no difference in the brain-to-plasma ratio in the Bcrp1(–/–) knockout mice (ratio range from 0.03 to 0.04) compared with wild-type mice. In contrast, Mdr1a/b(–/–)/Bcrp1(–/–) triple knockout mice had a 40-fold higher brain-to-plasma ratio (ratio range from 1.2 to 1.7), suggesting that Pgp and Bcrp work in concert to limit the brain-to-plasma ratio of lapatinib in mice. This finding has important potential consequences for the treatment of brain tumors in breast cancer patients treated with tyrosine kinase inhibitors as well as the basic understanding of ATP binding cassette transporters expressed in the blood-brain barrier on the central nervous system disposition of drugs. The American Society for Pharmacology and Experimental Therapeutics