Stephanie van Hoppe

57 Brain accumulation of osimertinib and its active metabolite is restricted by ABCB1 & ABCG2 Abcg2 plays an important role in AZ5104 transport across the BBB. At the same time, the equivalent parameters for AZ5104 in the liver were not significantly altered between the strains (Figure 5D-F). It thus appears that Abcb1a/1b and to a lesser extent also Abcg2 at the BBB can strongly restrict the brain accumulation of AZ5104. Figure 5 - Brain and liver concentration ( A, D ), tissue-to-plasma ratio ( B, E ) and relative tissue accumulation ( C, F ) of AZ5104 in male WT, Abcb1a/1b -/- , Abcg2 -/- , and Abcb1a/1b;Abcg2 -/- mice 1.5 h after oral administration of 10 mg/kg osimertinib. *, P < 0.05; **, P < 0.01; ***, P < 0.001 compared to WT mice. Data are presented as the mean ± SD. N = 5 mice per group. D I S C U S S I ON ABC efflux transporters, especially ABCB1 and ABCG2, have been shown to be associated with resistance to chemotherapy in several cancer cell lines, including NSCLC [25, 46]. Furthermore, brain metastases are a common occurrence in patients suffering from NSCLC [4-6, 47]. Because ABCB1 and ABCG2 are expressed at the BBB, these transporter proteins may play a significant role in limiting the pharmacotherapeutic treatment of cancer metastases in the brain. Given the recent therapeutic success of osimertinib in NSCLC patients, we wanted to investigate the possible effects of these transporters on osimertinib disposition. Figure 5. Brain and liver concentration ( A, D ), tissue-to-plasma ratio ( B, E ) and relative tissue accumulation ( C, F ) of AZ5104 in male WT, Abcb1a/1b -/- , Abcg2 -/- , and Abcb1a/1b;Abcg2 -/- mice 1.5 h after oral administration of 10 mg/kg osi ertinib. *, P < 0.05; **, P < 0.01; ***, P < 0.001 compared to WT mice. Data are presented as the mean ± SD. N = 5 mice per group. WT Abcb1a/1b-/- Abcg2 -/- Abcb1a/1b-/-; Abcg2-/- 0 100 200 300 400 500 Brain concentration (ng/g) *** *** *** *** *** WT Abcb1a/1b-/- Abcg2 -/- Abcb1a/1b-/-; Abcg2-/- 0 200 400 600 800 1000 Liver concentration (ng/g) WT Abcb1a/1b-/- Abcg2 -/- Abcb1a/1b-/-; Abcg2-/- 0 5 10 15 20 Brain to plasma ratio *** *** *** ** *** WT Abcb1a/1b-/- Abcg2 -/- Abcb1a/1b-/-; Abcg2-/- 0 10 20 30 40 Liver to plasma ratio WT Abcb1a/1b-/- Abcg2 -/- Abcb1a/1b-/-; Abcg2-/- 0 10 20 30 Brain accumulation (h -1 ) *** *** *** *** WT Abcb1a/1b-/- Abcg2 -/- Abcb1a/1b-/-; Abcg2-/- 0 10 20 30 40 50 Liver accumulation (h -1 ) AZ5104 A B C D E F