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1. J Pharmacol Exp Ther. 2012 Jan 11. [Epub ahead of print]

P-glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) restrict
brain accumulation of the active sunitinib metabolite N-desethyl sunitinib.

Tang SC, Lankheet NA, Poller B, Wagenaar E, Beijnen JH, Schinkel AH.

1 Division of Molecular Biology, The Netherlands Cancer Institute;

N-desethyl sunitinib is a major and pharmacologically active metabolite of the
tyrosine kinase inhibitor and anticancer drug sunitinib. Since 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, following
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 of 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 (13.7-fold) increased 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 only detectable in Abcb1a/1b(-/-)/Abcg2(-/-) mice
following sunitinib administration. Upon direct intravenous administration of
N-desethyl sunitinib, its plasma levels were 1.9-fold increased in Abcg2(-/-) and
Abcb1a/1b(-/-)/Abcg2(-/-) mice, suggesting that Abcg2 enhanced plasma clearance
of this metabolite. 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 as compared with its effect on sunitinib
brain accumulation.

PMID: 22238213 [PubMed - as supplied by publisher]