In vivo evaluation of P-glycoprotein and breast cancer resistance protein modulation in the brain using [11C]gefitinib

Evaluation of Limiting Brain Penetration Related to P-glycoprotein and Breast Cancer Resistance Protein Using [11C]GF120918 by PET in Mice

“…This suggests that the potent inhibitors P-gp and BCRP will improve brain penetration of therapeutic agents for targeting intracranial disease or malignancies [19]. We recently evaluated the in vivo brain penetration of [ 11 C]gefitinib combined with GF120918 in mice [20]. Developing [ 11 C] gefitinib as a positron emission tomography (PET) probe for evaluating P-gp and BCRP function is difficult because gefitinib is not a selective MDR modulator but instead is an inhibitor of epidermal growth factor receptor tyrosine kinase.…”

Interrogating Tumor Metabolism and Tumor Microenvironments Using Molecular Positron Emission Tomography Imaging. Theranostic Approaches to Improve Therapeutics

“…Gefitinib was labeled with 11 C and 18 F and evaluated in vitro and in vivo in xenografted mouse models (Su et al, 2008;Kawamura et al, 2009;Zhang et al, 2010). [ 18 F]Gefitinib had high nonspecific cellular uptake in vitro and did not correlate with EGFR expression levels in vivo (Su et al, 2008).…”

Interaction of innovative small molecule drugs used for cancer therapy with drug transporters

“…In vitro Animal models Dasatinib P-glycoprotein (ABCB1) CCRF-CEM cells (Hiwase et al, 2008), K562 cells (Hiwase et al, 2008;Hegedus et al, 2009;Haouala et al, 2010), MDCKII cells Lagas et al, 2009) Abcb1a/1b(-/-) mice (Lagas et al, 2009), Abcb1a/1b(-/-) Abcg2(-/-) mice Lagas et al, 2009) BCRP (ABCG2) K562 cells (Hiwase et al, 2008;Hegedus et al, 2009), MDCKII cells Lagas et al, 2009), murine fibroblast cell line MEF3.8 (Hiwase et al, 2008) Abcb1a/1b(-/-) Abcg2(-/-) mice Lagas et al, 2009) Erlotinib OAT3 (SLC22A8) HEK293 cells (Elmeliegy et al, 2011) OCT2 (SLC22A2) HEK293 cells (Elmeliegy et al, 2011) P-glycoprotein (ABCB1) LLC-PK1 cells (Marchetti et al, 2008;Kodaira et al, 2010), MDCKII cells (Marchetti et al, 2008) Abcb1a/1b(-/-) mice (Kodaira et al, 2010), de Vries et al, 2010;Kodaira et al, 2010) BCRP (ABCG2) HEK293 cells (Li et al, 2007), MDCKII cells (Marchetti et al, 2008;Kodaira et al, 2010), Saos2 cells (Elmeliegy et al, 2011) Abcg2(-/-) mice (Kodaira et al, 2010;Elmeliegy et al, 2011), Abcb1a/1b(-/-) Abcg2(-/-) mice (Marchetti et al, 2008;de Vries et al, 2010;Kodaira et al, 2010;Elmeliegy et al, 2011) Gefitinib P-glycoprotein (ABCB1) MDCKII cells (Agarwal et al, 2010) Abcb1a/1b(-/-) Abcg2(-/-) mice (Kawamura et al, 2009;Agarwal et al, 2010) BCRP (ABCG2) HEK293 cells (Li et al, 2007), MDCKII cells (Agarwal et al...…”

“…Stewart et al (2004) and Nakamura et al (2005) reported that gefitinib is not a substrate of human BCRP, whereas Li et al (2007) detected a significantly lower gefitinib accumulation in BCRP overexpressing HEK cells at lower concentrations. In vivo studies in knockout mice or using P-glycoprotein/Bcrp inhibitors revealed that transport of gefitinib across the blood-brain barrier is significantly limited by P-glycoprotein and Bcrp (Kawamura et al, 2009;Agarwal et al, 2010). Steady-state brain-to-plasma concentration ratios were 70-fold higher in the Abcb1a/1b(-/-) Abcg2(-/-) mice than in wild-type mice (Agarwal et al, 2010).…”