Stephanie van Hoppe

113 Brain accumulation of ponatinib and its active metabolite is limited by ABCB1 and ABCG2 looked at brain concentration and accumulation of DMP 2 h after oral administration of ponatinib, we obtained qualitatively similar results as in the 24 h experiment, although the quantitative effects were somewhat less pronounced (Supplementary Figure 4A-C). Overall, these data indicate that both mAbcg2 and mAbcb1a/1b contribute to restricting the brain accumulation of DMP, and can largely take over each other’s protective function at the BBB. On the other hand, Abcg2, but not Abcb1a/1b, appears to play a role in the elimination of DMP from plasma. Figure 5. Plasma concentration-time curves of DMP in female WT (black circles), Abcg triangles), Abcb1a/1b -/- (red triangles), and Abcg2;Abcb1a/1b -/- mice (blue squares) and Cy (yellow diamonds) over 24 hours ( A ) and the DMP:ponatinib plasma concentration ratio ( B ) administration of 10 mg/kg ponatinib. Data are given as mean ± SD (SD rendered one improved clarity). n = 4-5 mice per group. 0 4 8 12 16 20 24 0 10 20 30 40 50 Time (h) DMP plasma concentration (ng/ml) Wild-type Abcb1a/1b;Abcg2-/- Abcb1a/1b-/- Abcg2-/- Cyp3a-/- Time (h) DMP/ponatinib ratio in plasma 0 4 8 12 16 20 24 0.0 0.5 1.0 1.5 Wild-type Abcg2-/- Abcb1a/1b-/- Abcb1a/1b;Abcg2-/- Cyp3a-/- A B 0 4 8 0.00 0.06 0.12 Figure 5 - Plasma concentration-time curves of DMP in female WT (black circles), Abcg2 -/- (green triangles), Abcb1a/1b -/- (red triangles), and Abcg2;Abcb1a/1b -/- mice (blue squares) and Cyp3a -/- mice (yellow diamonds) over 24 hours ( A ) and the DMP:ponatinib plasma concentr tion ratio ( B ) after oral administration of 10 mg/kg ponatinib. Data are given s mean ± SD (SD r ndered one- sided for improved clarity). n = 4-5 mice per group.