Identification and characterization of endogenous biomarkers for hepatic vectorial transport (OATP1B3-P-gp) function using metabolomics with serum pharmacology
Abstract The organic anion-transporting polypeptide 1B3 and P-glycoprotein (P-gp) provide efficient directional transport (OATP1B3-P-gp) from the blood to the bile that serves as a key determinant of hepatic disposition of the drug. Unfortunately, there is still a lack of effective means to evaluate...
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| Format: | Article |
| Language: | English |
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Springer
2024-02-01
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| Series: | Amino Acids |
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| Online Access: | https://doi.org/10.1007/s00726-023-03363-5 |
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| author | Yong-wen Jin Yan-rong Ma Ming-kang Zhang Wen-bin Xia Pei Yuan Bo-xia Li Yu-hui Wei Xin-an Wu |
| author_facet | Yong-wen Jin Yan-rong Ma Ming-kang Zhang Wen-bin Xia Pei Yuan Bo-xia Li Yu-hui Wei Xin-an Wu |
| author_sort | Yong-wen Jin |
| collection | DOAJ |
| description | Abstract The organic anion-transporting polypeptide 1B3 and P-glycoprotein (P-gp) provide efficient directional transport (OATP1B3-P-gp) from the blood to the bile that serves as a key determinant of hepatic disposition of the drug. Unfortunately, there is still a lack of effective means to evaluate the disposal ability mediated by transporters. The present study was designed to identify a suitable endogenous biomarker for the assessment of OATP1B3-P-gp function in the liver. We established stably transfected HEK293T-OATP1B3 and HEK293T-P-gp cell lines. Results showed that azelaic acid (AzA) was an endogenous substrate for OATP1B3 and P-gp using serum pharmacology combined with metabolomics. There is a good correlation between the serum concentration of AzA and probe drugs of rOATP1B3 and rP-gp when rats were treated with their inhibitors. Importantly, after 5-fluorouracil-induced rat liver injury, the relative mRNA level and expression of rOATP1B3 and rP-gp were markedly down-regulated in the liver, and the serum concentration of AzA was significantly increased. These observations suggest that AzA is an endogenous substrate of both OATP1B3 and P-gp, and may serve as a potential endogenous biomarker for the assessment of the function of OATP1B3-P-gp for the prediction of changes in the pharmacokinetics of drugs transported by OATP1B3-P-gp in liver disease states. |
| format | Article |
| id | doaj-art-56fd653d00a14e8094769da03a1954b2 |
| institution | OA Journals |
| issn | 1438-2199 |
| language | English |
| publishDate | 2024-02-01 |
| publisher | Springer |
| record_format | Article |
| series | Amino Acids |
| spelling | doaj-art-56fd653d00a14e8094769da03a1954b22025-08-20T02:31:41ZengSpringerAmino Acids1438-21992024-02-0156111310.1007/s00726-023-03363-5Identification and characterization of endogenous biomarkers for hepatic vectorial transport (OATP1B3-P-gp) function using metabolomics with serum pharmacologyYong-wen Jin0Yan-rong Ma1Ming-kang Zhang2Wen-bin Xia3Pei Yuan4Bo-xia Li5Yu-hui Wei6Xin-an Wu7Department of Pharmacy, The First Hospital of Lanzhou UniversityDepartment of Pharmacy, The First Hospital of Lanzhou UniversitySchool of Pharmacy, Lanzhou UniversitySchool of Pharmacy, Lanzhou UniversityThe First Clinical Medical College, Lanzhou UniversityDepartment of Pharmacy, The First Hospital of Lanzhou UniversityDepartment of Pharmacy, The First Hospital of Lanzhou UniversityDepartment of Pharmacy, The First Hospital of Lanzhou UniversityAbstract The organic anion-transporting polypeptide 1B3 and P-glycoprotein (P-gp) provide efficient directional transport (OATP1B3-P-gp) from the blood to the bile that serves as a key determinant of hepatic disposition of the drug. Unfortunately, there is still a lack of effective means to evaluate the disposal ability mediated by transporters. The present study was designed to identify a suitable endogenous biomarker for the assessment of OATP1B3-P-gp function in the liver. We established stably transfected HEK293T-OATP1B3 and HEK293T-P-gp cell lines. Results showed that azelaic acid (AzA) was an endogenous substrate for OATP1B3 and P-gp using serum pharmacology combined with metabolomics. There is a good correlation between the serum concentration of AzA and probe drugs of rOATP1B3 and rP-gp when rats were treated with their inhibitors. Importantly, after 5-fluorouracil-induced rat liver injury, the relative mRNA level and expression of rOATP1B3 and rP-gp were markedly down-regulated in the liver, and the serum concentration of AzA was significantly increased. These observations suggest that AzA is an endogenous substrate of both OATP1B3 and P-gp, and may serve as a potential endogenous biomarker for the assessment of the function of OATP1B3-P-gp for the prediction of changes in the pharmacokinetics of drugs transported by OATP1B3-P-gp in liver disease states.https://doi.org/10.1007/s00726-023-03363-5OATP1B3P-gpEndogenous biomarkerMetabolomics |
| spellingShingle | Yong-wen Jin Yan-rong Ma Ming-kang Zhang Wen-bin Xia Pei Yuan Bo-xia Li Yu-hui Wei Xin-an Wu Identification and characterization of endogenous biomarkers for hepatic vectorial transport (OATP1B3-P-gp) function using metabolomics with serum pharmacology Amino Acids OATP1B3 P-gp Endogenous biomarker Metabolomics |
| title | Identification and characterization of endogenous biomarkers for hepatic vectorial transport (OATP1B3-P-gp) function using metabolomics with serum pharmacology |
| title_full | Identification and characterization of endogenous biomarkers for hepatic vectorial transport (OATP1B3-P-gp) function using metabolomics with serum pharmacology |
| title_fullStr | Identification and characterization of endogenous biomarkers for hepatic vectorial transport (OATP1B3-P-gp) function using metabolomics with serum pharmacology |
| title_full_unstemmed | Identification and characterization of endogenous biomarkers for hepatic vectorial transport (OATP1B3-P-gp) function using metabolomics with serum pharmacology |
| title_short | Identification and characterization of endogenous biomarkers for hepatic vectorial transport (OATP1B3-P-gp) function using metabolomics with serum pharmacology |
| title_sort | identification and characterization of endogenous biomarkers for hepatic vectorial transport oatp1b3 p gp function using metabolomics with serum pharmacology |
| topic | OATP1B3 P-gp Endogenous biomarker Metabolomics |
| url | https://doi.org/10.1007/s00726-023-03363-5 |
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