title: The role of efflux and uptake transporters in [N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, lapatinib) disposition and drug interactions.
abstract: Lapatinib [N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine, GW572016, Tykerb] is a tyrosine kinase inhibitor approved for use in combination with capecitabine to treat advanced or metastatic breast cancers overexpressing HER2 (ErbB2). In this work we investigated the role of efflux and uptake transporters in lapatinib disposition and drug interactions. In vitro studies evaluated whether lapatinib is a substrate for efflux transporters or an inhibitor of efflux/uptake transporters. In vivo studies included whole-body autoradiography and an evaluation of the role of efflux transporters on the intestinal absorption and brain penetration of lapatinib using chemical or genetic knockout animals. Lapatinib is a substrate for the efflux transporters P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Furthermore, lapatinib is an inhibitor (IC(50) values 0.025-5 muM) of Pgp, BCRP, and organic anion transporting polypeptide 1B1 (a hepatic uptake transporter). In contrast, lapatinib yielded little inhibition on renal transporters (organic anion transporters, organic cation transporters, and uric acid transporter). In vivo studies demonstrated that brain concentrations of lapatinib were low and influenced by efflux transporters at the blood-brain barrier. In contrast, systemic exposure of lapatinib after oral dosing was unchanged when efflux by Pgp and BCRP was absent from the gastrointestinal tract. These in vitro and in vivo preclinical investigations provide a mechanistic basis for elucidating clinical drug interactions.
authors.affiliation: Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Inc., P.O. Box 13398, Room MAI.A2213, Research Triangle Park, NC 27709, USA. joseph.w.polli@gsk.com
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Polli
authors.forename: Joan E
authors.initials: JE
authors.lastname: Humphreys
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Harmon
authors.forename: Stephen
authors.initials: S
authors.lastname: Castellino
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Mara
authors.forename: Katie L
authors.initials: KL
authors.lastname: Olson
authors.forename: Lisa St
authors.initials: LS
authors.lastname: John-Williams
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Koch
authors.forename: Cosette J
authors.initials: CJ
authors.lastname: Serabjit-Singh
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D000077341:Lapatinib; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution / Q000502:physiology
chemical_list: D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D011799:Quinazolines; D000077341:Lapatinib