Stephanie van Hoppe

120 Chapter 5 S U P P L EME N TA R Y MAT E R I A L Supplementary Figure 1 - Schematic representation of the main metabolites formed from ponatinib in humans. The main ponatinib metabolite, carboxylic acid (AP24600), is formed by esterase- and/ or amidase-mediated hydrolysis. Two other pharmacodynamically active metabolites formed by Cytochrome P450 (mainly CYP3A4) are N-desmethyl ponatinib (DMP, AP24567) and N-oxide ponatinib (AP24734). Supplementary Figure 2 - Brain to liver ratio at 2 h (A) and 24 h (B) in female WT, Abcg2 -/- , Abcb1a/1b -/- and Abcg2;Abcb1a/1b -/- mice after oral administration of 10 mg/kg ponatinib. *, P < 0.05; **, P< 0.01; ***, P < 0.001 compared to WT mice. Data are given as mean ± SD. N = 3-5 mice per group. Supplementary Figure 1. Schematic representation of the main metabolites formed from ponatinib in humans. The main ponatinib metabolite, carboxylic acid (AP24600), is formed by esterase- and/or amidase-mediated hydrolysis. Two other pharmacodynamically active metabolites formed by Cytochrome P450 (mainly CYP3A4) are N-desmethyl ponatinib (DMP, AP24567) and N-oxide ponatinib (AP24734). AP24567 N-desmethyl ponatinib (DMP) Ponatinib Esterase- and/or amidase-mediated hydrolysis AP24734 N-oxide ponatinib Cytochrome P450 (mainly CYP3A4) Cytochrome P450 (mainly CYP3A4) AP24600 carboxylic acid Supplementary Figure 2 . Brain to liver ratio at 2 h (A) and 24 h (B) in female WT, Abcg2 -/- , Abcb1a/1b - /- and Abcg2;Abcb1a/1b -/- mice after oral administration of 10 mg/kg ponatinib. *, P < 0.05; **, P< 0.01; ***, P < 0.001 co pared to WT mice. Data are given as mean ± SD. N = 3-5 mice per group. A B 2 hours after oral administration Wild-type Abcg2-/- Abcb1a/1b-/- Abcb1a/1b;Abcg2-/- Cyp3a-/- 0.0 0.2 0.4 0.6 0.8 Brain to liver ratio 24 hours after oral administration Wild-type Abcg2-/- Abcb1a/1b-/- Abcb1a/1b;Abcg2-/- 0.0 0.1 0.2 0.3 0.4 Brain to liver ratio *** *** 15-fold 19-fold