Table 1.

List of molecularly targeted and nontargeted agents examined for treatment of glioblastoma and their P-gp/BCRP substrate status reported as brain-to-plasma ratio (B/P) determined in wild-type mice compared with knockout (KO) mice lacking expression of P-gp or BCRP or both

Drug	Molecular Target	Substrate Status		B/P in Mouse Models				References
		P-gp	BCRP	Wild-type Mouse B/P	P-gp KO Mouse B/P	BCRP KO Mouse B/P	Combined P-gp/BCRP KO B/P
Targeted agents
Erlotiniba	EGFR	Yes	Yes	0.14	0.41	0.14	0.58	38
Tandutiniba	PDGFR, FLT3	Yes	Yes		∼3.2 fold	∼0.9 fold	∼13.5 fold	39
Gefitinibb	EGFR	Yes	Yes	0.07 ± 0.02			7.3 ± 0.5	40
Cediranibb	VEGFR	Yes	Yes	0.25 ± 0.10	5.2 ± 1.1	0.27 ± 0.01	6.3 ± 1.2	41
Sorafenibb,c	Raf kinase, VEGFR, PDGFR	Yes	Yes	0.094 ± 0.007b, 5.3 ± 2.7c	0.11 ± 0.02b, 5.8 ± 2.2c	0.36 ± 0.06b, 22.6 ± 5.0c	0.91 ± 0.29b, 49.4 ± 5.2c	65,66
Vandetanibd	VEGFR, EGFR	Yes	Yes	0.21			0.64	42
Pazopanibd	VEGFR, PDGFR, c-kit	Yes	Yes	0.015			0.041	67
Dasatiniba,c	BCR-Abl, EGFR	Yes	Yes	6.39 ± 1.39c, 0.12a	22.7 ± 5.41c	5.11 ± 0.7c	84.3 ± 13.3c, 0.93a	41,68
Sunitinibb,c	VEGFR, PDGFR, c-kit	Yes	Yes	1.6 ± 1.0c, 0.51 ± 0.26b	2.8 ± 0.8c, 2.33 ± 0.56b	2.4 ± 0.9c, 0.73 ± 0.44b	42.4 ± 10.7c, 17.44 ± 5.08b	69,70
Imatinibe,f,g	BCR-Abl, PDGFR, c-kit	Yes	Yes		∼2.73 folde, ∼3.6 foldg, ∼5.5 foldf	∼2.5 folde		71–73
Lapatinibb	EGFR	Yes	Yes	0.03 ± 0.01	0.09 ± 0.02	0.04 ± 0.01	1.2 ± 0.42	74
Everolimusa	mTOR	Yes	NA		∼1.3 fold			75
GNE-317h	Dual PI3 K/mTOR	No	No	1.01 ± 0.05				35
GDC-0980i	Dual PI3 K/mTOR	Yes	Yes	0.082 ± 0.008			1.0 ± 0.20	76
GDC-0941g	PI3K	Yes	No		∼2.24 fold	∼1.05 fold	∼29.42 fold	77
Axitinibc	VEGFR-1, -2, -3	Yes	Yes	94.8 ± 27	643.6 ± 183.2	47.7 ± 12.7	1315 ± 375	78
Nontargeted agents
Vincristineb	Vinca alkaloid	Yes	No		∼2.1 fold		∼3.5 fold	79
Cisplatin	Platinum-based drug	Yes	Yes					80
Doxorubicinj	Anthracycline topoisomerase inhibitor	Yes	Yes		∼3.3 fold			81
Paclitaxelk	Microtubule inhibitor	Yes	No		∼7.9 fold			82
Irinotecana	Topoisomerase inhibitor	Yes	Yes		∼2.1 fold			83
Topotecana	Topoisomerase inhibitor	Yes	Yes	0.32	0.64	0.21	1.02	84

Abbreviations: EGFR, epidermal growth factor receptor; PDGFR, platelet derived growth factor receptor; FLT3, Fms-like tyrosine kinase 3; VEGFR, vascular endothelial growth factor receptor; BCR-Abl, breakpoint cluster region–Abelson murine leukemia; NA, not available (not yet established in mouse studies).

^aArea under the concentration (AUC) time curve ratios obtained as AUC_∞ brain-to-AUC_∞ plasma.

^bSteady state brain-to-plasma concentration ratios.

^cBrain penetration, ie, Pbrain = relative brain accumulation at 6 h after oral administration, calculated by determining the brain concentration relative to plasma AUC_0-6.

^dBrain-to-plasma concentration ratio obtained after administration with a dual inhibitor (GF120918) of P-gp and BCRP.

^eB/P ratios not available.

^fUsing in situ brain perfusion to determine fold increase.

^gDetermined at a single time point post oral dose.

^hDetermined at 2 time points; 1 h after oral dose; B/P ratio in absence of P-gp and BCRP was not reported.

ⁱDetermined at 2 time points, 1 h and 6 h post-dose; here we report 1 h after oral dose.

^jDetermined at a single time point post i.v. dose.

^kAUC ratio obtained as AUC_0-24, _brain-to-AUC_0-8, _plasma.