Article Figures & Data
Figures
- Fig. 1.
Transepithelial transport of dasatinib (5 μmol/L) was assessed in MDCK-II cells either nontransduced (A and D) or transduced with murine Abcg2 (B) or human ABCB1 (C) or ABCC2 (E) cDNA. At t = 0 h, dasatinib was applied in one compartment (apical or basolateral), and the concentration in the opposite compartment at t = 2 and 4 h was measured by LC-MS/MS and plotted as the percentage of initial drug concentration (n = 3). D and E, elacridar (5 μmol/L) was applied to inhibit endogenous P-gp. ▴, translocation from the basolateral to the apical compartment; □, translocation from the apical to the basolateral compartment. Points, mean; bars, SD. At t = 4 h, 1% of transport is approximately equal to an apparent permeability coefficient (Papp) of 0.30 × 10−6 cm/s.
- Fig. 2.
Plasma concentration-time curves of dasatinib in male FVB WT (▪), Abcg2−/− (□), Abcb1a/1b−/− (Δ), and Abcb1a/1b;Abcg2−/− (▴) mice after oral (A) and i.p. (B) administration of dasatinib at a dose of 10 mg/kg (oral) and 5 mg/kg (i.p.). Points, mean (n = 5 for oral and n = 4 for i.p. administration); bars, SD.
- Fig. 3.
Relative brain accumulation of dasatinib in male FVB WT, Abcg2−/−, Abcb1a/1b−/−, and Abcb1a/1b;Abcg2−/− mice after oral (A) or i.p. (B) administration of dasatinib at a dose of 10 mg/kg (oral) or 5 mg/kg (i.p.). Relative brain accumulation was calculated by determining the brain concentration relative to AUC0-6. Columns, mean (n = 5 for oral and n = 4 for i.p. administration); bars, SD. ***, P < 0.001, compared with WT mice.
- Fig. 4.
Plasma (A) and brain (B) concentrations and brain-to-plasma ratios (C) for FVB WT and Abcb1a/1b;Abcg2−/− (KO) mice 60 min after i.v. administration of 5 mg/kg dasatinib. Dasatinib was given 15 min after the i.v. administration of either vehicle or elacridar (10 mg/kg). Columns, mean (n = 4 for WT and n = 3 for KO); bars, SD. *, P < 0.05; **, P < 0.01; ***, P < 0.001, compared with WT mice treated with vehicle.
Tables
Time (min) 0.0 0.5 3.0 6.0 6.1 8.0 8.1 12.0 Eluent B (%) 55 55 80 80 100 100 55 55 - Table 1.
Plasma pharmacokinetic parameters after oral (10 mg/kg) or i.p. (5 mg/kg) administration of dasatinib
Strain WT Abcb1a/1b−/− Abcg2−/− Abcb1a/1b;Abcg2−/− Oral AUC(0-6) (mg/L.h) 1.02 ± 0.27 1.70 ± 0.42* 1.00 ± 0.35 2.05 ± 0.25† Cmax (mg/L) 0.37 ± 0.08 0.49 ± 0.27 0.31 ± 0.21 0.70 ± 0.22* Tmax (h) 2 0.5 2 0.25 CLapp (L/h.kg) 10.4 ± 2.40 6.15 ± 1.38† 11.0 ± 3.61 4.94 ± 0.58† I.p. AUC(0-6) (mg/L.h) 1.59 ± 0.10 1.25 ± 0.15* 1.69 ± 0.32 1.52 ± 0.16 Cmax (mg/L) 0.94 ± 0.07 0.81 ± 0.06 0.86 ± 0.07 0.81 ± 0.03* t1/2, el (h) 0.93 ± 0.04 1.43 ± 0.49 0.98 ± 0.28 1.33 ± 0.12* CLapp (L/h.kg) 3.16 ± 0.20 4.05 ± 0.50* 3.05 ± 0.66 3.31 ± 0.36 Frel (%) 32.0 ± 1.74 68.0 ± 3.72† 29.6 ± 2.39 67.3 ± 2.13† NOTE: Data are means ± SD, n = 5 for oral and n = 4 for i.p. administration. All parameters obtained for KO mice were compared with those for WT mice.
Abbreviations: Cmax, maximum plasma levels; t1/2, el, elimination half-life, calculated from 2 to 6 h; CLapp, apparent clearance (CL/F); Frel, relative oral bioavailability.
↵* P < 0.05, compared with WT mice.
↵† P < 0.01, compared with WT mice.
- Table 2.
Brain concentrations and relative brain accumulation after oral (10 mg/kg) or i.p. (5 mg/kg) administration of dasatinib
Strain WT Abcb1a/1b−/− Abcg2−/− Abcb1a/1b;Abcg2−/− Oral Cbrain (ng/g) 6.50 ± 2.10 37.2 ± 5.38* 4.93 ± 1.13 171.6 ± 30.9* Pbrain (×10−3 h−1) 6.39 ± 1.39 22.7 ± 5.41* 5.11 ± 0.68 84.3 ± 13.3* I.p. Cbrain (ng/g) 5.47 ± 0.38 25.6 ± 3.56* 5.15 ± 1.73 116.7 ± 15.2* Pbrain (×10−3 h−1) 3.44 ± 0.17 16.4 ± 1.71* 2.78 ± 0.65 78.1 ± 18.8* NOTE: Data are means ± SD, n = 5 for oral and n = 4 for i.p. administration. All parameters obtained for KO mice were compared with those for WT mice.
Abbreviations: Cbrain, brain concentration at 6 h after administration; Pbrain, relative brain accumulation at 6 h after administration, calculated by determining the dasatinib brain concentration relative to AUC0-6.
↵* P < 0.001, compared with WT mice.
Volume 15, Issue 7
