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- Title
A Metabolomics Approach for Predicting OATP1B-Type Transporter-Mediated Drug–Drug Interaction Liabilities.
- Authors
Li, Yang; Jin, Yan; Taheri, Hanieh; Schmidt, Keith T.; Gibson, Alice A.; Buck, Stefan A. J.; Eisenmann, Eric D.; Mathijssen, Ron H. J.; Figg, William D.; Baker, Sharyn D.; Sparreboom, Alex; Hu, Shuiying
- Abstract
In recent years, various endogenous compounds have been proposed as putative biomarkers for the hepatic uptake transporters OATP1B1 and OATP1B3 that have the potential to predict transporter-mediated drug–drug interactions (DDIs). However, these compounds have often been identified from top–down strategies and have not been fully utilized as a substitute for traditional DDI studies. In an attempt to eliminate observer bias in biomarker selection, we applied a bottom–up, untargeted metabolomics screening approach in mice and found that plasma levels of the conjugated bile acid chenodeoxycholate-24-glucuronide (CDCA-24G) are particularly sensitive to deletion of the orthologous murine transporter Oatp1b2 (31-fold increase vs. wild type) or the entire Oatp1a/1b(−/−)cluster (83-fold increased), whereas the humanized transgenic overexpression of hepatic OATP1B1 or OATP1B3 resulted in the partial restoration of transport function. Validation studies with the OATP1B1/OATP1B3 inhibitors rifampin and paclitaxel in vitro as well as in mice and human subjects confirmed that CDCA-24G is a sensitive and rapid response biomarker to dose-dependent transporter inhibition. Collectively, our study confirmed the ability of CDCA-24G to serve as a sensitive and selective endogenous biomarker of OATP1B-type transport function and suggests a template for the future development of biomarkers for other clinically important xenobiotic transporters.
- Subjects
DRUG interactions; PACLITAXEL; METABOLOMICS; BILE acids; BIOMARKERS; RIFAMPIN; FORECASTING
- Publication
Pharmaceutics, 2022, Vol 14, Issue 9, pN.PAG
- ISSN
1999-4923
- Publication type
Article
- DOI
10.3390/pharmaceutics14091933