Substrate-dependent effects of molecular-targeted anticancer agents on activity of organic anion transporting polypeptide 1B1. 2018

Hiroyoshi Koide, and Masayuki Tsujimoto, and Ai Takeuchi, and Miyu Tanaka, and Yoko Ikegami, and Mayu Tagami, and Syoko Abe, and Miki Hashimoto, and Tetsuya Minegaki, and Kohshi Nishiguchi
a Department of Clinical Pharmacy , Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University , Kyoto , Japan.

1. Organic anion-transporting polypeptide 1B1 (OATP1B1) plays an important role in the hepatic uptake of a broad range of substrate drugs. In vitro experiments show that molecular-targeted agents do not always have similar effects on OATP1B1 activity. 2. The purpose of this study was to clarify whether the effects of molecular-targeted agents on OATP1B1 are substrate-dependent. We used OATP1B1-transfected cells to compare the effects of molecular-targeted agents on OATP1B1-mediated uptake of fluorescein (FL), 2',7'-dichlorofluorescein (DCF), atorvastatin, SN-38 and valsartan. 3. Cabozantinib, cediranib, neratinib, pazopanib, regorafenib, sorafenib and tivantinib did not affect or only slightly affected OATP1B1-mediated substrate uptake. Nilotinib and lenvatinib moderately and strongly inhibited OATP1B1-mediated substrate uptake, respectively. In contrast, afatinib stimulated OATP1B1-mediated uptake of FL and SN-38, ceritinib stimulated that of valsartan, and nintedanib stimulated that of FL and valsartan. In addition, the effects of afatinib, ceritinib and nintedanib on OATP1B1 activity differed markedly depending on the type of substrate. Afatinib, ceritinib and nintedanib had a substrate-dependent effect on OATP1B1 activity. 4. We conclude that the evaluation of OATP1B1 activity using only a single probe substrate for some molecular-targeted agents may lead to a faulty understanding of their mechanisms of drug interactions.

UI MeSH Term Description Entries
D007700 Kinetics The rate dynamics in chemical or physical systems.
D004347 Drug Interactions The action of a drug that may affect the activity, metabolism, or toxicity of another drug. Drug Interaction,Interaction, Drug,Interactions, Drug
D005452 Fluoresceins A family of spiro(isobenzofuran-1(3H),9'-(9H)xanthen)-3-one derivatives. These are used as dyes, as indicators for various metals, and as fluorescent labels in immunoassays. Tetraiodofluorescein
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D013379 Substrate Specificity A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts. Specificities, Substrate,Specificity, Substrate,Substrate Specificities
D057809 HEK293 Cells A cell line generated from human embryonic kidney cells that were transformed with human adenovirus type 5. 293T Cells,HEK 293 Cell Line,HEK 293 Cells,Human Embryonic Kidney Cell Line 293,Human Kidney Cell Line 293,293 Cell, HEK,293 Cells, HEK,293T Cell,Cell, 293T,Cell, HEK 293,Cell, HEK293,Cells, 293T,Cells, HEK 293,Cells, HEK293,HEK 293 Cell,HEK293 Cell
D058990 Molecular Targeted Therapy Treatments with drugs which interact with or block synthesis of specific cellular components characteristic of the individual's disease in order to stop or interrupt the specific biochemical dysfunction involved in progression of the disease. Targeted Molecular Therapy,Molecular Targeted Therapies,Molecular Therapy, Targeted,Targeted Molecular Therapies,Targeted Therapy, Molecular,Therapy, Molecular Targeted,Therapy, Targeted Molecular
D019793 Fluorescein A phthalic indicator dye that appears yellow-green in normal tear film and bright green in a more alkaline medium such as the aqueous humor. Fluorescein Sodium,Sodium Fluorescein,C.I. 45350,Colircusi Fluoresceina,D & C Yellow No. 7,D & C Yellow No. 8,D and C Yellow No. 7,D and C Yellow No. 8,D&C Yellow No. 7,D&C Yellow No. 8,Diofluor,Disodium Fluorescein,Fluor-I-Strip A.T.,Fluorescein Dipotassium Salt,Fluorescein Disodium Salt,Fluorescein Monosodium Salt,Fluorescite,Fluorescéine sodique Faure,Fluorets,Ful-Glo,Funduscein,Minims Fluorescein Sodium,Minims Fluoresceine,Minims Stains,Optifluor Diba,Uranine,Dipotassium Salt, Fluorescein,Disodium Salt, Fluorescein,Fluor I Strip A.T.,Fluorescein Sodium, Minims,Fluorescein, Disodium,Fluorescein, Sodium,Fluoresceina, Colircusi,Fluoresceine, Minims,Ful Glo,Monosodium Salt, Fluorescein,Sodium, Fluorescein
D020128 Inhibitory Concentration 50 The concentration of a compound needed to reduce population growth of organisms, including eukaryotic cells, by 50% in vitro. Though often expressed to denote in vitro antibacterial activity, it is also used as a benchmark for cytotoxicity to eukaryotic cells in culture. IC50,Concentration 50, Inhibitory

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