PT-019 - ROLE OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 1B (OATP1B) IN HEPATIC UPTAKE AND ADVERSE EFFECTS OF AROMATASE INHIBITORS (AIS).

H. Taheri¹, Y. Li¹, Y. Jin¹, A. Gibson¹, M. B. Lustbergb², A. Sparreboom¹, S. Hu¹; ¹The Ohio State University, Columbus, OH, USA, ²Yale University, New Haven, CT, USA.

Background: AIs (Anastrozole, Letrozole, Exemestane) are widely used in post-menopausal women with breast cancer. Despite their specificity, significant toxicities including arthralgia affect quality of life and limit effectiveness. The mechanism(s) by which AIs are taken up into liver and thereby regulate plasma levels, tissue distribution, as well as toxicity remains unknown. In this study, we explored the hypothesis that OATP1B-type transporter activity affects the pharmacokinetics of AIs and their dose-limiting side effect arthralgia.

Methods: In vitro uptake studies were performed in cells expressing human OATP1B1/1B3 or mouse OATP1B2. Biomarkers identified from untargeted metabolomics analysis in samples from wild-type and OATP1B2(-/-) mice were measured in baseline plasma samples from 20 patients treated with AIs with or without arthralgia symptoms. Pharmacokinetic studies were performed in wild-type, OATP1B2(-/-), and humanized transgenic mice receiving AIs (1-20 mg/kg; p.o.).

Results: Hepatic levels of several endogenous OATP1B2 substrates, including chenodeoxycholate-24-glucuronide (CDCA-24G), were reduced in OATP1B2(-/-) mice. Levels of CDCA-24G were also significantly associated (P < 0.01) with higher risk of arthralgia in patients. The interaction of the AIs letrozole and exemestane with OATPs was verified in our in vitro and in vivo models.

Conclusion: In this study, we demonstrated that OATP1B activity as reflected by endogenous biomarkers is directly related to plasma levels of AIs and treatment-related arthralgia. Our currently ongoing studies are focused on the influence of OATP1B inhibitors on the plasma and liver levels of AIs, as well as the influence of OATP1B-deficiency on AIs-associated arthralgia using imaging, mechanical, and behavioral tests.