Stephanie van Hoppe

78 Chapter 4 To investigate the impact of single and combined knockout of Abcb1a/1b and Abcg2 on ibrutinib brain distribution, we isolated mouse tissues (brain, liver, kidneys, spleen) at the end of the 1 h pharmacokinetic experiment. Figure 3A shows that ibrutinib accumulated to a low extent in the brain of WT and Abcg2 -/- mice, but more highly in Abcb1a/1b -/- and Abcb1a/1b;Abcg2 -/- mice. Correction for the substantial differences in plasma concentration at 1 h and the plasma AUCs showed that brain-to-plasma ratios and brain accumulation of ibrutinibweremarkedly (and highly significantly) increased in both the Abcb1-deficient strains, but not in the single Abcg2-deficient strain (Figure 3B and C). In contrast, analysis of the liver, which often equilibrates rapidly with drug levels in plasma, yielded no significant differences in liver-to-plasma ratio or liver accumulation Figure 2. Plasma concentration−time curves of ibrutinib ( A ) and ibrutinib-DiOH (DiOH) ( B ) in female WT (black circles), Abcb1a/1b −/− (blue squares), Abcg2 −/− (dark blue triangles) and Abcb1a/1b;Abcg2 −/− (green triangles) mice over 1 h after oral administration of 10 mg/kg ibrutinib. Note the difference in Y-axis scales between the panels. Data are given as mean ± SD. n = 5−6 mice per group. 0.0 0.5 1.0 0 200 400 600 800 1000 time (hours) Ibrutinib ng/ml WT Abcb1a/1b -/- Abcg2 -/- Abcb1a/1b;Abcg2 -/- A B WT Abcb1a/1b -/- Abcg2 -/- Abcb1a/1b;Abcg2 -/- 0.0 0.5 1.0 0 500 1000 1500 2000 time (hours) DiOH ng/ml Figure 2 - Plasma concentration−time curves of ibrutinib ( A ) and ibruti ib-DiOH (DiO ) ( B ) in female WT (black circles), Abcb1a/1b −/− (blue squares), Abcg2 −/− (dark blue triangles) and Abcb1a/1b;Abcg2 −/− (green triangles) mice over 1 h after oral administration of 10 mg/kg ibrutinib. Note the difference in Y-axis scales between the panels. Data are given as mean ± SD. n = 5−6 mice per group.