A Metabolomics Approach for Predicting OATP1B-Type Transporter-Mediated Drug–Drug Interaction Liabilities
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 str...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-09-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/9/1933 |
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| author | Yang Li Yan Jin Hanieh Taheri Keith T. Schmidt Alice A. Gibson Stefan A. J. Buck Eric D. Eisenmann Ron H. J. Mathijssen William D. Figg Sharyn D. Baker Alex Sparreboom Shuiying Hu |
| author_facet | Yang Li Yan Jin Hanieh Taheri Keith T. Schmidt Alice A. Gibson Stefan A. J. Buck Eric D. Eisenmann Ron H. J. Mathijssen William D. Figg Sharyn D. Baker Alex Sparreboom Shuiying Hu |
| author_sort | Yang Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T22:49:54Z |
| format | Article |
| id | doaj.art-f5ac3357508f42909be4461d3b90d944 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T22:49:54Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-f5ac3357508f42909be4461d3b90d9442023-11-23T18:23:13ZengMDPI AGPharmaceutics1999-49232022-09-01149193310.3390/pharmaceutics14091933A Metabolomics Approach for Predicting OATP1B-Type Transporter-Mediated Drug–Drug Interaction LiabilitiesYang Li0Yan Jin1Hanieh Taheri2Keith T. Schmidt3Alice A. Gibson4Stefan A. J. Buck5Eric D. Eisenmann6Ron H. J. Mathijssen7William D. Figg8Sharyn D. Baker9Alex Sparreboom10Shuiying Hu11Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USADivision of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USADivision of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USAClinical Pharmacology Program, Office of the Clinical Director, National Cancer Institute, Bethesda, ML 20892, USADivision of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USADepartment of Medical Oncology, Erasmus Medical Center Cancer Institute, Dr. Molewaterplein 40, 3015 GD Rotterdam, The NetherlandsDivision of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USADepartment of Medical Oncology, Erasmus Medical Center Cancer Institute, Dr. Molewaterplein 40, 3015 GD Rotterdam, The NetherlandsClinical Pharmacology Program, Office of the Clinical Director, National Cancer Institute, Bethesda, ML 20892, USADivision of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USADivision of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USADivision of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USAIn 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.https://www.mdpi.com/1999-4923/14/9/1933endogenous biomarkersOATP1Btaxanedrug–drug interactions |
| spellingShingle | Yang Li Yan Jin Hanieh Taheri Keith T. Schmidt Alice A. Gibson Stefan A. J. Buck Eric D. Eisenmann Ron H. J. Mathijssen William D. Figg Sharyn D. Baker Alex Sparreboom Shuiying Hu A Metabolomics Approach for Predicting OATP1B-Type Transporter-Mediated Drug–Drug Interaction Liabilities Pharmaceutics endogenous biomarkers OATP1B taxane drug–drug interactions |
| title | A Metabolomics Approach for Predicting OATP1B-Type Transporter-Mediated Drug–Drug Interaction Liabilities |
| title_full | A Metabolomics Approach for Predicting OATP1B-Type Transporter-Mediated Drug–Drug Interaction Liabilities |
| title_fullStr | A Metabolomics Approach for Predicting OATP1B-Type Transporter-Mediated Drug–Drug Interaction Liabilities |
| title_full_unstemmed | A Metabolomics Approach for Predicting OATP1B-Type Transporter-Mediated Drug–Drug Interaction Liabilities |
| title_short | A Metabolomics Approach for Predicting OATP1B-Type Transporter-Mediated Drug–Drug Interaction Liabilities |
| title_sort | metabolomics approach for predicting oatp1b type transporter mediated drug drug interaction liabilities |
| topic | endogenous biomarkers OATP1B taxane drug–drug interactions |
| url | https://www.mdpi.com/1999-4923/14/9/1933 |
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