title: Role of P-glycoprotein in intestinal absorption of FB2, a promising Abl/Src dual tyrosine kinase inhibitor.
abstract: 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 (P-gp) in intestinal absorption of FB2 with an in vitro Caco-2 and MDCK-MDR1 cell model, single-pass intestinal perfusion model and in vivo pharmacokinetics with a 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 the 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 the rat intestine.
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Bejing, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.forename: Jinping
authors.initials: J
authors.lastname: Hu
authors.forename: Xue
authors.initials: X
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D018938:Caco-2 Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D014700:Verapamil / Q000493:pharmacokinetics; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C556348:FB2 compound; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D014700:Verapamil; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases