title: Effect of P-glycoprotein and breast cancer resistance protein inhibition on the pharmacokinetics of sunitinib in rats.
abstract: The aim of this study was to elucidate the roles of P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) in the plasma concentration, biliary excretion, and distribution to the liver, kidney, and brain of sunitinib. The pharmacokinetics of sunitinib was examined in rats treated with PSC833 (valspodar) and pantoprazole, potent inhibitors of P-gp and BCRP, respectively. The sunitinib concentrations in plasma, bile, liver, kidney, and brain were determined by liquid chromatography-tandem mass spectrometry. It was found that the area under the concentration-time curve for 4 hours (AUC0-4) and maximum concentration (Cmax) of sunitinib administered intraintestinally were significantly increased by pretreatment with PSC833 or pantoprazole. Each inhibitor markedly reduced the biliary excretion of sunitinib for 60 minutes after an intravenous administration and significantly increased the distribution of sunitinib to the liver as well as kidney. In addition, the brain distribution of sunitinib was significantly increased by PSC833 but not pantoprazole, and coadministration of both inhibitors further enhanced the accumulation of sunitinib in the brain. These results demonstrate that plasma concentrations of sunitinib and the biliary excretion and distribution to the kidney, liver, and brain of sunitinib are influenced by pharmacologic inhibition of P-gp and/or BCRP.
authors.affiliation: Department of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kunimatsu
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Mizuno
authors.forename: Masahide
authors.initials: M
authors.lastname: Fukudo
authors.forename: Toshiya
authors.initials: T
authors.lastname: Katsura
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000494:pharmacology; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000502:physiology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001646:Bile / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D007211:Indoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D000077402:Pantoprazole; D011758:Pyrroles / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000077210:Sunitinib; D014018:Tissue Distribution
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000255:Adenosine Triphosphate; D000077402:Pantoprazole; D000077210:Sunitinib