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Eur J Med Chem. 2015 Mar 6;92:723-31. doi: 10.1016/j.ejmech.2015.01.011. Epub 2015 Jan 8.

Interaction of human organic anion transporter polypeptides 1B1 and 1B3 with antineoplastic compounds.

Author information

1
Institut für Vegetative Physiologie und Pathophysiologie, Universitätsmedizin Göttingen, Humboldtallee 23, 37073 Göttingen, Germany. Electronic address: venkata.marada@med.uni-goettingen.de.
2
PortaCellTec Biosciences GmbH, Humboldtallee 23, 37073 Göttingen, Germany. Electronic address: floerl@portacelltec.de.
3
PortaCellTec Biosciences GmbH, Humboldtallee 23, 37073 Göttingen, Germany. Electronic address: kuehne@portacelltec.de.
4
Institut für Vegetative Physiologie und Pathophysiologie, Universitätsmedizin Göttingen, Humboldtallee 23, 37073 Göttingen, Germany. Electronic address: gerhard.burckhardt@med.uni-goettingen.de.
5
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.

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.

KEYWORDS:

Antineoplastic compounds; Drug transporter interactions; Organic anion transporting polypeptide 1B1; Organic anion transporting polypeptide 1B3; Uptake transporter proteins

PMID:
25618019
DOI:
10.1016/j.ejmech.2015.01.011
[Indexed for MEDLINE]

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