title: Nilotinib concentration in cell lines and primary CD34(+) chronic myeloid leukemia cells is not mediated by active uptake or efflux by major drug transporters.
abstract: Imatinib mesylate and nilotinib are highly effective at eradicating the majority of chronic myeloid leukemia (CML) cells; however, neither agent induces apoptosis of primitive CML CD34(+) cells. One possible explanation is that CD34(+) cells do not accumulate sufficient intracellular drug levels because of either inadequate active uptake or increased efflux. To determine the interaction of nilotinib with major clinically implicated drug transporters, we analyzed their interactions with MDR1 (ABCB1), MRP1 (ABCC1), ABCG2 (BCRP) and human organic cation transporter (hOCT)1 in CML cell lines and primitive (CD34(+)) primary CML cells. Nilotinib is neither dependent on active import by hOCT1, nor effluxed through the ATP-binding cassette transporters analyzed. Indeed, we found nilotinib to be an inhibitor of hOCT1, MDR1 and ABCG2. The efflux transporters MDR1, MRP1 and ABCG2 are expressed on CML CD34(+) cells at 13.5, 108 and 291% of control, respectively, although hOCT1 expression was absent; however, inhibition of efflux transporter activity did not potentiate the effect of nilotinib on apoptosis, Bcr-Abl inhibition or CML CD34(+) cell proliferation. Therefore, we have found no evidence for either active uptake of nilotinib through hOCT1 or efflux through MDR1, MRP1 or ABCG2, and it is therefore unlikely that these transporters will have any effect on the clinical response to this drug.
authors.affiliation: Department of Haematology, Royal Liverpool University Hospital, Liverpool, UK.
authors.forename: A
authors.initials: A
authors.lastname: Davies
authors.forename: N E
authors.initials: NE
authors.lastname: Jordanides
authors.forename: A
authors.initials: A
authors.lastname: Giannoudis
authors.forename: C M
authors.initials: CM
authors.lastname: Lucas
authors.forename: S
authors.initials: S
authors.lastname: Hatziieremia
authors.forename: R J
authors.initials: RJ
authors.lastname: Harris
authors.forename: H G
authors.initials: HG
authors.lastname: Jørgensen
authors.forename: T L
authors.initials: TL
authors.lastname: Holyoake
authors.forename: M
authors.initials: M
authors.lastname: Pirmohamed
authors.forename: R E
authors.initials: RE
authors.lastname: Clark
authors.forename: J C
authors.initials: JC
authors.lastname: Mountford
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D001693:Biological Transport, Active / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004285:Dogs; D006801:Humans; D000068877:Imatinib Mesylate; D007668:Kidney / Q000166:cytology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008051:Lipid Bilayers / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000378:metabolism; D010879:Piperazines / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000493:pharmacokinetics*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001549:Benzamides; D002352:Carrier Proteins; D000068877:Imatinib Mesylate; D008051:Lipid Bilayers; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D027702:Organic Cation Transporter 1; D010879:Piperazines; D011743:Pyrimidines; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C498826:nilotinib; C421109:multidrug resistance-associated protein 1