Stephanie van Hoppe

108 Chapter 5 Table 1 - Pharmacokinetic parameters of ponatinib and DMP at 24 h after oral administration of 10 mg/kg ponatinib to female wild-type, Abcg2 -/- , Abcb1a/1b -/- , Abcb1a/1b;Abcg2 -/- and Cyp3a -/- mice. Parameter Genotype Compound Wild-type Abcg2 -/- Abcb1a/1b -/- Abcb1a/1b;Abcg2 -/- Cyp3a -/- Plasma AUC (0-24) , h.ng/mL Ponatinib 2378 ± 293 2660 ± 383 2421 ± 395 2602 ± 188 3312 ± 486** Fold increase AUC (0-24) 1.0 1.1 1.0 1.1 1.4 C max , ng/mL 181 ± 26 201 ± 42 138 ± 49 210 ± 56 251 ± 69 T max , h 4 - 8 2 - 8 4 - 8 2 - 8 4 - 8 C brain , ng/g 22 ± 8 49 ± 7** 42 ± 19* 558 ± 109*** 21 ± 4 Fold increase C brain 1.0 2.2 1.9 25.5 1.0 P brain (*10 -3 h -1 ) 9.0 ± 2.5 19 ± 2.9** 17 ± 6.6* 215 ± 46*** 6.9 ± 1.3 Fold increase P brain 1.0 2.2 1.9 24 0.8 Plasma AUC (0-24) , h.ng/mL DMP 139 ± 15 445 ± 116*** 199 ± 31 544 ± 85*** 163 ± 44 Fold increase AUC (0-24) 1.0 3.2 1.4 3.9 1.2 C max , ng/mL 11 ± 1.0 32 ± 7.4 13 ± 5.7 37 ± 6.8 13 ± 5.5 T max , h 4 - 8 4 - 8 4 - 8 4 - 8 4 - 8 C brain , ng/g 6.1 ± 2.8 13 ± 3.5** 10 ± 2.7 354 ± 26*** 6.3 ± 1.6 Fold increase C brain 1.0 2.1 1.6 58 1.0 P brain (*10 -3 h -1 ) 43 ± 18 29 ± 6.6* 51 ± 10 659 ± 83*** 44 ± 5.8 Fold increase P brain 1.0 0.7 1.2 15 1.0 AUC, area under the plasma concentration-time curve; C max maximum concentration in plasma; T max , the time after drug administration needed to reach maximum plasma concentration; C brain , brain concentration; P brain , brain accumulation (C brain divided by plasma AUC); C liver , liver concentration; P liver , liver accumulation (C liver divided by plasma AUC). *, P < 0.05; **, P < 0.01; ***, P < 0.001 compared to WT mice. Data are given as mean ± SD. All groups consisted of n = 4-5 mice.