Identification and characterization of endogenous biomarkers for hepatic vectorial transport (OATP1B3-P-gp) function using metabolomics with serum pharmacology.

Autor: Jin YW; Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, 730000, China.; The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, China., Ma YR; Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, 730000, China., Zhang MK; School of Pharmacy, Lanzhou University, Lanzhou, China., Xia WB; School of Pharmacy, Lanzhou University, Lanzhou, China., Yuan P; The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, China., Li BX; Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, 730000, China., Wei YH; Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, 730000, China., Wu XA; Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, 730000, China. wuxa@lzu.edu.cn.; School of Pharmacy, Lanzhou University, Lanzhou, China. wuxa@lzu.edu.cn.
Jazyk: angličtina
Zdroj: Amino acids [Amino Acids] 2024 Feb 06; Vol. 56 (1), pp. 11. Date of Electronic Publication: 2024 Feb 06.
DOI: 10.1007/s00726-023-03363-5
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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