P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) Restrict Brain Accumulation of the Active Sunitinib MetaboliteN-Desethyl Sunitinib

Abstract

N-desethyl sunitinib is a major and pharmacologically active metabolite of the tyrosine kinase inhibitor and anticancer drug sunitinib. Because the combination of N-desethyl sunitinib and sunitinib represents total active drug exposure, we investigated the impact of several multidrug efflux transporters on plasma pharmacokinetics and brain accumulation of N-desethyl sunitinib after sunitinib administration to wild-type and transporter knockout mice. In vitro, N-desethyl sunitinib was a good transport substrate of human ABCB1 and ABCG2 and murine Abcg2, but not ABCC2 or Abcc2. At 5 M, ABCB1 and ABCG2 contributed almost equally to N-desethyl sunitinib transport. In vivo, the systemic exposure of N-desethyl sunitinib after oral dosing of sunitinib malate (10 mg/kg) was unchanged when Abcb1 and/or Abcg2 were absent. However, brain accumulation of N-desethyl sunitinib was markedly increased (13.7-fold) in Abcb1a/1b(Ϫ/Ϫ)/ Abcg2(Ϫ/Ϫ) mice, but not in Abcb1a/1b(Ϫ/Ϫ) or Abcg2(Ϫ/Ϫ) mice. In the absence of the ABCB1 and ABCG2 inhibitor elacridar, brain concentrations of N-desethyl sunitinib were detectable only in Abcb1a/1b(Ϫ/Ϫ)/Abcg2(Ϫ/Ϫ) mice after sunitinib administration. Combined elacridar plus N-desethyl sunitinib treatment increased N-desethyl sunitinib plasma and brain exposures, but not brain-to-plasma ratios in wild-type mice. In conclusion, brain accumulation of N-desethyl sunitinib is effectively restricted by both Abcb1 and Abcg2. The effect of elacridar treatment in improving brain accumulation of N-desethyl sunitinib in wild-type mice was limited compared with its effect on sunitinib brain accumulation.

Brain and Testis Accumulation of Regorafenib is Restricted by Breast Cancer Resistance Protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1)

“…We found that absence of Abcb1a/1b and Abcg2 does not affect oral availability, but does influence brain and testis accumulation of regorafenib. Similar effects have been described previously for example with sorafenib, sunitinib and CYT387 (14,28,33). Additionally, we found a significant detectable impact of single Abcb1a/1b knockout on the regorafenib accumulation in the testis, while there was a slight but insignificant impact of Abcb1a/1b absence in the brain.…”

“…We think that our findings can be a good source for future clinical studies of cancer patients with CNS involvement, as we here showed a clear impact of ABCB1 and ABCG2 in restricting brain penetration of regorafenib. Moreover, based on our previous experience (14,20,28), we suggest that combined administration of regorafenib with ABCB1 and ABCG2 inhibitors such as elacridar might improve the brain concentration and thus efficacy of regorafenib against metastases located behind an intact BBB.…”

“…Lowering the concentration to 1 μM was enough to demonstrate that regorafenib was indeed a transported substrate of hABCG2. As discussed before (14,27,28), a lower in vitro transport capacity of hABCG2 versus mAbcg2 that is consistently seen for many drugs in these cells may relate to the difficulty in obtaining MDCKII cell lines with a high hABCG2 expression and activity. Another possibility is that the Km of regorafenib for hABCG2 is lower than that for mAbcg2.…”

Management of dose variability and side effects for individualized cancer pharmacotherapy with tyrosine kinase inhibitors

“…The pharmacokinetic role of ABCG2 and ABCB1 was also shown using Abcg2 −/− , Abcb1a/1b −/− and Abcg2 −/− /Abcb1a/1b −/− mice Tang et al, 2012Tang et al, , 2013. For example, we demonstrated that the maximum concentration and AUC 0-4 of sunitinib were significantly higher in Abcg2 −/− , Abcb1a/1b −/− and Abcg2 −/− /Abcb1a/1b −/− mice than in wild-type ones when sunitinib was given orally, but not intraperitoneally .…”

Apicobasal polarity of brain endothelial cells

“…83 According to the same line of evidence, MRP4 (ABCC4) and BCRP (ABCG2) are also mainly localized in the apical/luminal membrane of brain endothelial cells (Figure 2). 35,84 . Density-gradient centrifugation of membranes By using density-gradient centrifugation brain capillary membranes can be fractionated to obtain purified preparations of apical/luminal and basolateral/abluminal membranes.…”