title: The effect of P-gp (Mdr1a/1b), BCRP (Bcrp1) and P-gp/BCRP inhibitors on the in vivo absorption, distribution, metabolism and excretion of imatinib.
abstract: Imatinib is transported by P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), however, the exact impact of these transporters on absorption, distribution, metabolism and excretion (ADME) of imatinib is not fully understood due to incomplete data. We have performed a comprehensive ADME study of imatinib given as single agent or in combination with the well known BCRP/P-gp inhibitors, elacridar and pantoprazole, in wild-type and P-gp and/or BCRP knockout mice. The absence of P-gp and BCRP together resulted in a significantly higher area under the plasma concentration-time curve (AUC) after i.v. administration, whereas the AUC after oral dosing was unaltered. Both elacridar and pantoprazole significantly increased the AUC of orally administered imatinib in wild-type but also in P-gp/BCRP knockout mice. This lower clearance was not due to a (further) reduction in biliary excretion. Fecal excretion was significantly reduced in P-gp and P-gp/BCRP knockout but not in BCRP knockout mice, whereas the brain penetration was significantly higher in P-gp/BCRP knockout mice compared to single P-gp or BCRP knockout or wild-type mice. In conclusion, P-gp and BCRP have only a modest effect on the ADME of imatinib in comparison to metabolic elimination. P-gp is the most prevalent factor for systemic clearance and limiting the brain penetration. The considerable drug-drug interaction observed with elacridar or pantoprazole is only partly mediated by inhibition of P-gp and BCRP and far more by the inhibition of other elimination pathways.
authors.affiliation: Division of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands. r.oostendorp@nki.nl
authors.forename: Roos L
authors.initials: RL
authors.lastname: Oostendorp
authors.forename: Tessa
authors.initials: T
authors.lastname: Buckle
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Olaf
authors.initials: O
authors.lastname: van Tellingen
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000494:pharmacology; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics; D000042:Absorption; D000166:Acridines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001549:Benzamides; D001646:Bile / Q000737:chemistry; D001921:Brain / Q000187:drug effects; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005243:Feces / Q000737:chemistry; D005260:Female; D000068877:Imatinib Mesylate; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D000077402:Pantoprazole; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D000166:Acridines; D000970:Antineoplastic Agents; D001549:Benzamides; C464561:CGP 74588; D004338:Drug Combinations; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D044005:Tetrahydroisoquinolines; D000068877:Imatinib Mesylate; D000077402:Pantoprazole; C083501:Elacridar