RT Journal Article
SR Electronic
T1 P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) Restrict Brain Accumulation of the Active Sunitinib Metabolite <em>N</em>-Desethyl Sunitinib
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 164
OP 173
DO 10.1124/jpet.111.186908
VO 341
IS 1
A1 Seng Chuan Tang
A1 Nienke A. G. Lankheet
A1 Birk Poller
A1 Els Wagenaar
A1 Jos H. Beijnen
A1 Alfred H. Schinkel
YR 2012
UL http://jpet.aspetjournals.org/content/341/1/164.abstract
AB 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 μM, 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(−/−)/Abcg2(−/−) mice, but not in Abcb1a/1b(−/−) or Abcg2(−/−) mice. In the absence of the ABCB1 and ABCG2 inhibitor elacridar, brain concentrations of N-desethyl sunitinib were detectable only in Abcb1a/1b(−/−)/Abcg2(−/−) 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.