pgp - publications

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1. Drug Metab Pharmacokinet. 2012 Mar 22. [Epub ahead of print]

Role of P-glycoprotein in intestinal absorption of FB2, a promising Abl/Src dual
tyrosine kinase inhibitor.

Huang K, Hu J, Li X, Li Y.

Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union
Medical College.

FB2 is a promising Abl/Src dual tyrosine kinase inhibitor which is designed to
overcome imatinib resistance. The present study aims to investigate the role of
P-glycoprotein in intestinal absorption of FB2 by in vitro Caco-2 and MDCK-MDR1
cell model, single-pass intestinal perfusion model and in vivo pharmacokinetics
with selective inhibitor in rats. The results from Caco-2 cells indicated that
P(appB-A) of FB2 and its metabolites (FB7 and FB10)( )were much higher than
P(appA-B, )and the efflux ratio (P(appB-A)/P(appA-B)) of FB2, FB7 and FB10 were
decreased with P-gp inhibitor LSN335984, FB2 was further confirmed to be the
substrate of P-gp in MDCK-MDR1 cells. In addition, P(blood )of FB2 and cumulative
amount of metabolites in mesenteric blood were elevated in a
concentration-dependent manner in rat intestinal perfusion, while both of them
were remarkably increased when P-gp inhibitor was added. The F(oral) of FB2 was
increased to 24.52% when orally coadministrated with verapamil (25 mg/kg), which
was significantly higher than that (5.7%) by FB2 (18 mg/kg) alone in rats. The
AUC and Cmax of FB2 metabolites (FB7 and FB10) were also increased in the
presence of verapamil. In conclusion, the low bioavailability of FB2 is believed
to be partially due to the P-gp mediated active efflux and first-pass metabolism
in rat intestine.

PMID: 22447116 [PubMed - as supplied by publisher]