PT  - JOURNAL ARTICLE
AU  - Tang, Seng Chuan
AU  - Lankheet, Nienke A. G.
AU  - Poller, Birk
AU  - Wagenaar, Els
AU  - Beijnen, Jos H.
AU  - Schinkel, Alfred H.
TI  - P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) Restrict Brain Accumulation of the Active Sunitinib Metabolite <em>N</em>-Desethyl Sunitinib
AID  - 10.1124/jpet.111.186908
DP  - 2012 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 164--173
VI  - 341
IP  - 1
4099  - http://jpet.aspetjournals.org/content/341/1/164.short
4100  - http://jpet.aspetjournals.org/content/341/1/164.full
SO  - J Pharmacol Exp Ther2012 Apr 01; 341
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.