understanding what limits/allows the brain penetration of lapatinib(tykerb)

[Lani]

Drug Metab Dispos. 2008 Dec 4. [Epub ahead of print]

An Unexpected Synergist Role of P-glycoprotein and Breast Cancer Resistance Protein on the CNS Penetration of the Tyrosine Kinase Inhibitor Lapatinib (GW572016).

Polli JW, Olson KL, Chism JP, St John-Williams LA, Yeager RL, Woodard SM, Otto VR, Castellino S, Demby VE.
GlaxoSmithKline.
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 (HER2, 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 CNS penetration of lapatinib at steady state conditions in FVBn mice (wild-type), Mdr1a/b(-/-), Bcrp1(-/-) and Mdr1a/b(-/-)/Bcrp1(-/-) knockout mice. Following an intravenous infusion of lapatinib for 24 hours 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 0.09 to 0.16) compared to wild-type mice (ratio range 0.03 to 0.04). There was no difference in the brain-to-plasma ratio in the Bcrp1(-/-) knockout mice (ratio range 0.03 to 0.04) compared to wild-type mice. In contrast, Mdr1a/b(-/-)/Bcrp1(-/-) triple knockout mice had a 40-fold higher brain-to-plasma ratio (ratio range 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 ABC transporters expressed in the blood-brain barrier on the central nervous system disposition of drugs.
PMID: 19056914