ABSTRACT: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 brainto-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 brainto-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.Lapatinib (Tykerb, GW572016) is a novel member of the 4-anilinoquinazoline class of tyrosine kinase inhibitors (TKI) (Boyd et al., 2005;Johnston and Leary, 2006;Moy and Goss, 2006). It is a dual inhibitor of both epidermal growth factor receptor (ErbB) 1 and human epidermal receptor (HER) 2 with IC 50 values of approximately 10 nM against the purified receptors in vitro, and it potently inhibits growth of epidermal growth factor receptor and/or HER2-overexpressing tumors both in vitro and in vivo. Lapatinib is approved for use in combination with other anticancer agents for the treatment of HER2-positive breast cancers (Geyer et al., 2006).A particular challenge to the treatment of breast cancer, particularly HER2-overexpressing tumors, is central nervous system (CNS) metastases. Up to 35% of patients with HER2-positive advanced breast cancer relapse due to intracranial disease, despite control of the peripheral tumors (Weil et al., 2005). CNS tumors are difficult to treat due to limited brain and/or tumor exposure of most anticancer agents. Nonclinical data suggest that the brain concentrations of lapatinib and other TKIs are low due to efflux transporters in the blood-brain barrier (Heimberger et al., 2002;Breedveld et al., 2005;Kil et al., 2007;Polli et al., 2008). These nonclinical data imply that TKIs may have limited Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.108.024646. La...
