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

Venkata V V R Marada1, Saskia Flörl2, Annett Kühne2

  • 1Institut für Vegetative Physiologie und Pathophysiologie, Universitätsmedizin Göttingen, Humboldtallee 23, 37073 Göttingen, Germany.

European Journal of Medicinal Chemistry
|January 26, 2015
PubMed

Insights

This study reveals how cancer drugs interact with liver transport proteins Organic Anion Transporting Polypeptide 1B1 (OATP1B1) and OATP1B3. Understanding these interactions is crucial for effective cancer chemotherapy and avoiding drug-drug interactions.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Biochemistry

Background:

  • Antineoplastic compounds are vital for cancer treatment, with their efficacy influenced by cellular transport proteins.
  • Organic anion transporting polypeptide 1B1 (OATP1B1) and OATP1B3 are key liver proteins involved in drug transport.
  • Interactions between antineoplastic drugs and these transporters can significantly impact treatment outcomes.

Purpose of the Study:

  • To investigate the interactions between commonly used antineoplastic compounds and the OATP1B1 and OATP1B3 transporter proteins.
  • To characterize the functional activity of OATP1B1 and OATP1B3 in the context of cancer chemotherapy agents.
  • To identify novel interactions that may inform drug development and clinical practice.

Main Methods:

  • Functional characterization of OATP1B1 and OATP1B3 in stably transfected human embryonic kidney cells.
  • Utilized [(3)H] labeled estrone 3-sulfate and [(3)H] labeled cholecystokinin octapeptide (CCK-8) as substrates for OATP1B1 and OATP1B3, respectively.
  • Performed substrate uptake experiments in the presence of various antineoplastic compounds to determine inhibitory effects (Ki values).

Main Results:

  • Vinblastine and paclitaxel showed strong interactions with OATP1B1 (Ki values 10.2 μM and 0.84 μM, respectively).
  • OATP1B3 exhibited significant interactions with multiple antineoplastic agents, including chlorambucil, mitoxantrone, vinblastine, vincristine, paclitaxel, and etoposide, with Ki values ranging from 1.8 μM to 40.6 μM.
  • Several novel interactions between antineoplastic drugs and OATP1B1/OATP1B3 were identified.

Conclusions:

  • The study identified significant interactions between OATP1B1 and OATP1B3 with several clinically relevant antineoplastic drugs.
  • These findings underscore the importance of considering transporter-drug interactions in cancer chemotherapy.
  • Further investigation into the role of OATP1B1 and OATP1B3 is warranted to optimize cancer treatment strategies and manage potential drug-drug interactions.
Keywords:
Antineoplastic compoundsDrug transporter interactionsOrganic anion transporting polypeptide 1B1Organic anion transporting polypeptide 1B3Uptake transporter proteins

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