title: Interaction of human organic anion transporter polypeptides 1B1 and 1B3 with antineoplastic compounds.
abstract: Antineoplastic compounds are used in the treatment of a variety of cancers. The effectiveness of an antineoplastic compound to exert its activity is largely dependent on transport proteins involved in the entry of the compound into the cells, and those which drive it out of the cell. Organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3), belonging to the SLCO family of proteins, are specifically expressed in the sinusoidal membranes of the liver, and are known to interact with a variety of drugs. The present study deals with the interaction of these proteins with antineoplastic compounds routinely used in cancer chemotherapy. The proteins OATP1B1 and OATP1B3 were functionally characterized in stably transfected human embryonic kidney cells using [(3)H] labeled estrone 3-sulfate and [(3)H] labeled cholecystokinin octapeptide (CCK-8) as substrates, respectively. Substrate uptake experiments performed in the presence of antineoplastic compounds showed that vinblastine and paclitaxel strongly interacted with the OATP1B1 with Ki values of 10.2 μM and 0.84 μM, respectively. OATP1B3 showed highly significant interactions with a variety of antineoplastic compounds including chlorambucil, mitoxantrone, vinblastine, vincristine, paclitaxel and etoposide, with Ki values of 40.6 μM, 3.2 μM, 15.9 μM, 30.6 μM, 1.8 μM and 13.5 μM, respectively. We report several novel interactions of the transporter proteins OATP1B1 and OATP1B3 highlighting the need to investigate their role in drug-drug interactions and cancer chemotherapy.
authors.affiliation: Institut für Vegetative Physiologie und Pathophysiologie, Universitätsmedizin Göttingen, Humboldtallee 23, 37073 Göttingen, Germany. Electronic address: venkata.marada@med.uni-goettingen.de.
authors.forename: Venkata V V R
authors.initials: VV
authors.lastname: Marada
authors.affiliation: PortaCellTec Biosciences GmbH, Humboldtallee 23, 37073 Göttingen, Germany. Electronic address: floerl@portacelltec.de.
authors.forename: Saskia
authors.initials: S
authors.lastname: Flörl
authors.affiliation: PortaCellTec Biosciences GmbH, Humboldtallee 23, 37073 Göttingen, Germany. Electronic address: kuehne@portacelltec.de.
authors.forename: Annett
authors.initials: A
authors.lastname: Kühne
authors.affiliation: Institut für Vegetative Physiologie und Pathophysiologie, Universitätsmedizin Göttingen, Humboldtallee 23, 37073 Göttingen, Germany. Electronic address: gerhard.burckhardt@med.uni-goettingen.de.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Burckhardt
authors.affiliation: Institut für Vegetative Physiologie und Pathophysiologie, Universitätsmedizin Göttingen, Humboldtallee 23, 37073 Göttingen, Germany; PortaCellTec Biosciences GmbH, Humboldtallee 23, 37073 Göttingen, Germany. Electronic address: hagos@physiol.med.uni-goettingen.de.
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Hagos
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D015394:Molecular Structure; D027361:Organic Anion Transporters / Q000737:chemistry / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D010455:Peptides; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
keywords: Antineoplastic compounds; Drug transporter interactions; Organic anion transporting polypeptide 1B1; Organic anion transporting polypeptide 1B3; Uptake transporter proteins