Stephanie van Hoppe

79 ABCB1 restricts brain penetration of the BTK inhibitor ibrutinib while CYP3A limits its oral bioavailability (Figure 3D-F). Together, these data indicate that Abcb1a/1b markedly restricts brain accumulation of ibrutinib. Whether Abcg2 also contributes to this process is uncertain, as the (modest) differences between the Abcb1a/1b -/- and Abcb1a/1b;Abcg2 -/- brains were not statistically significant (Figure 3B and C). The intrinsic brain accumulation of ibrutinib was quite low inWT mice, with a brain-to-plasma ratio of 0.081, which however rose to about 0.37 to 0.48 in the Abcb1a/1b -/- or the combination Abcb1a/1b;Abcg2 -/- strain, respectively (Figure 3B, Table 1). Compared to a liver-to-plasma ratio of 1.4-1.5 at this time point (Figure 3E), this suggests a fairly good brain penetration of this drug, but only when Abcb1a/1b is absent. Figure 3. Brain and liver concentration ( A, D ), tissue-to-plasma ratio ( B, E ) and relative tissue accumulation ( C, F ) of ibrutinib in female WT, Abcb1a/1b −/− , Abcg2 −/− and Abcb1a/1b;Abcg2 −/− mice 1 h after oral administration of 10 mg/kg ibrutinib. *, P < 0.05; **, P < 0.01; ***, P < 0.001 compared to WT mice. Data are given as mean ± SD. n = 5−6 mice per group. ** **** **** * **** A B C D E F WT Abcg2 -/- Abcb1a/1b -/- Abcb1a/1b;Abcg2 -/- 0 10 20 30 40 Ibrutinib brain concentration (ng/g) WT Abcg2 -/- Abcb1a/1b -/- Abcb1a/1b;Abcg2 -/- 0 100 200 300 Ibrutinib liver concentration ng/g WT Abcg2 -/- Abcb1a/1b -/- Abcb1a/1b;Abcg2 -/- 0.0 0.2 0.4 0.6 ibrutinib brain to plasma ratio WT Abcg2 -/- Abcb1a/1b -/- Abcb1a/1b;Abcg2 -/- 0.0 0.5 1.0 1.5 2.0 Ibrutinib liver to plasma ratio WT Abcg2 -/- Abcb1a/1b -/- Abcb1a/1b;Abcg2 -/- 0.00 0.05 0.10 0.15 0.20 0.25 Ibrutinib brain accumulation (h -1 ) WT Abcg2 -/- Abcb1a/1b -/- Abcb1a/1b;Abcg2 -/- 0.0 0.2 0.4 0.6 0.8 Ibrutinib liver accumulation (h -1 ) 1-hour experiment ** * Figure 3 - Brain and liver concen ration ( A, D ), tissue-to-plasma ratio ( B, E ) nd relative tissue a cumulation ( C, F ) of ibrutinib in female WT, Abcb1a/1b −/− , Abcg2 −/− and Abc 1a/1b;Abcg2 −/− mice 1 h after oral administration of 10 mg/kg ibrutinib. *, P < 0.05; **, P < 0.01; ***, P < 0.001 compared to WT mice. Data are given as mean ± SD. n = 5−6 mice per group.