title: Assessment of Amino Acid/Drug Transporters for Renal Transport of [18F]Fluciclovine (anti-[18F]FACBC) in Vitro.
abstract: [18F]Fluciclovine (trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid;anti-[18F]FACBC), a positron emission tomography tracer used for the diagnosis of recurrent prostate cancer, is transported via amino acid transporters (AATs) with high affinity (Km: 97-230 μM). However, the mechanism underlying urinary excretion is unknown. In this study, we investigated the involvement of AATs and drug transporters in renal [18F]fluciclovine reuptake. [14C]Fluciclovine (trans-1-amino-3-fluoro[1-14C]cyclobutanecarboxylic acid) was used because of its long half-life. The involvement of AATs in [14C]fluciclovine transport was measured by apical-to-basal transport using an LLC-PK1 monolayer as model for renal proximal tubules. The contribution of drug transporters herein was assessed using vesicles/cells expressing the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance-associated protein 4 (MRP4), organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3) , organic cation transporter 2 (OCT2), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporting polypeptide 1B3 (OATP1B3). The apical-to-basal transport of [14C]fluciclovine was attenuated by l-threonine, the substrate for system alanine-serine-cysteine (ASC) AATs. [14C]Fluciclovine uptake by drug transporter-expressing vesicles/cells was not significantly different from that of control vesicles/cells. Fluciclovine inhibited P-gp, MRP4, OAT1, OCT2, and OATP1B1 (IC50> 2.95 mM). Therefore, system ASC AATs may be partly involved in the renal reuptake of [18F]fluciclovine. Further, given that [18F]fluciclovine is recognized as an inhibitor with millimolar affinity for the tested drug transporters, slow urinary excretion of [18F]fluciclovine may be mediated by system ASC AATs, but not by drug transporters.
authors.affiliation: Research Center, Nihon Medi-Physics Co., Ltd., Chiba 299-0266, Japan. masahiro_ono@nmp.co.jp.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ono
authors.affiliation: Research Center, Nihon Medi-Physics Co., Ltd., Chiba 299-0266, Japan. atsumi_baden@nmp.co.jp.
authors.forename: Atsumi
authors.initials: A
authors.lastname: Baden
authors.affiliation: Research Center, Nihon Medi-Physics Co., Ltd., Chiba 299-0266, Japan. hiroyuki_okudaira@nmp.co.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okudaira
authors.affiliation: Wellness Promotion Science Center, Institute of Medical, Pharmaceutical and Health Science, Kanazawa University, Ishikawa 920-0942, Japan. kobayasi@mhs.mp.kanazawa-u.ac.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Division of Health Sciences, Graduate School of Medical Sciences, Kanazawa University, Ishikawa 920-0942, Japan. kei@mhs.mp.kanazawa-u.ac.jp.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kawai
authors.affiliation: Research Center, Nihon Medi-Physics Co., Ltd., Chiba 299-0266, Japan. shuntaro_oka@nmp.co.jp.
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Oka
authors.affiliation: Research Center, Nihon Medi-Physics Co., Ltd., Chiba 299-0266, Japan. hirokatsu_yoshimura@nmp.co.jp.
authors.forename: Hirokatsu
authors.initials: H
authors.lastname: Yoshimura
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism; D026905:Amino Acid Transport Systems / Q000378:metabolism*; D001692:Biological Transport; D002264:Carboxylic Acids / Q000378:metabolism*; D002460:Cell Line; D003503:Cyclobutanes / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D026905:Amino Acid Transport Systems; D002264:Carboxylic Acids; D003503:Cyclobutanes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C116614:ABCG2 protein, human; C117460:fluciclovine F-18
keywords: amino acid transporter; anti-FACBC; drug transporter; fluciclovine; positron emission tomography