Albumin-bound kynurenic acid is an appropriate endogenous biomarker for assessment of the renal tubular OATs-MRP4 channel

Yanrong Ma; Fenglin Ran; Mingyan Xin; Xueyan Gou; Xinyi Wang; Xinan Wu

doi:10.1016/j.jpha.2023.05.007

Volume 13 Issue 10

Oct. 2023

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Yanrong Ma, Fenglin Ran, Mingyan Xin, Xueyan Gou, Xinyi Wang, Xinan Wu. Albumin-bound kynurenic acid is an appropriate endogenous biomarker for assessment of the renal tubular OATs-MRP4 channel[J]. Journal of Pharmaceutical Analysis, 2023, 13(10): 1205-1220. doi: 10.1016/j.jpha.2023.05.007

Citation:

Yanrong Ma, Fenglin Ran, Mingyan Xin, Xueyan Gou, Xinyi Wang, Xinan Wu. Albumin-bound kynurenic acid is an appropriate endogenous biomarker for assessment of the renal tubular OATs-MRP4 channel[J]. Journal of Pharmaceutical Analysis, 2023, 13(10): 1205-1220. doi: 10.1016/j.jpha.2023.05.007

Citation:

Yanrong Ma, Fenglin Ran, Mingyan Xin, Xueyan Gou, Xinyi Wang, Xinan Wu. Albumin-bound kynurenic acid is an appropriate endogenous biomarker for assessment of the renal tubular OATs-MRP4 channel[J]. Journal of Pharmaceutical Analysis, 2023, 13(10): 1205-1220. doi: 10.1016/j.jpha.2023.05.007

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Albumin-bound kynurenic acid is an appropriate endogenous biomarker for assessment of the renal tubular OATs-MRP4 channel

doi: 10.1016/j.jpha.2023.05.007

a. The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China;
b. School of Pharmacy, Lanzhou University, Lanzhou, 730000, China

Funds:

This research was supported by the National Natural Science Foundation of China (Grant Nos.: 81803611, 82160705, and U21A20424) and the Natural Science Foundation of Gansu Province, China (Grant No.: 21ZD4FA014).

Received Date: Jan. 03, 2023
Accepted Date: May 12, 2023
Rev Recd Date: May 08, 2023
Publish Date: Oct. 30, 2023

Abstract

Abstract

Renal tubular secretion mediated by organic anion transporters (OATs) and the multidrug resistance-associated protein 4 (MRP4) is an important means of drug and toxin excretion. Unfortunately, there are no biomarkers to evaluate their function. The aim of this study was to identify and characterize an endogenous biomarker of the renal tubular OATs-MRP4 channel. Twenty-six uremic toxins were selected as candidate compounds, of which kynurenic acid was identified as a potential biomarker by assessing the protein-binding ratio and the uptake in OAT1-, OAT3-, and MRP4-overexpressing cell lines. OAT1/3 and MRP4 mediated the transcellular vectorial transport of kynurenic acid in vitro. Serum kynurenic acid concentration was dramatically increased in rats treated with a rat OAT1/3 (rOAT1/3) inhibitor and in rOAT1/3 double knockout (rOAT1/3^-/-) rats, and the renal concentrations were markedly elevated by the rat MRP4 (rMRP4) inhibitor. Kynurenic acid was not filtered at the glomerulus (99% of albumin binding), and was specifically secreted in renal tubules through the OAT1/3-MRP4 channel with an appropriate affinity (K_m) (496.7 μM and 382.2 μM for OAT1 and OAT3, respectively) and renal clearance half-life (t_1/2) in vivo (3.7 ± 0.7 h). There is a strong correlation in area under the plasma drug concentration-time curve (AUC) between cefmetazole and kynurenic acid, but not with creatinine, after inhibition of rOATs. In addition, the phase of increased kynurenic acid level is earlier than that of creatinine in acute kidney injury process. These results suggest that albumin-bound kynurenic acid is an appropriate endogenous biomarker for adjusting the dosage of drugs secreted by this channel or predicting kidney injury.
- Transporter,
- Biomarker,
- Kynurenic acid,
- Renal tubular excretion

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References(53)

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