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Mechanistic Study on the Effect of Renal Impairment on the Pharmacokinetics of Vildagliptin and its Carboxylic Acid Metabolite

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Abstract

Purpose

To clarify the mechanism of renal impairment leading to different degrees of increased plasma exposure to dipeptidyl peptidase 4 inhibitor vildagliptin and its major metabolite, M20.7.

Methods

The 5/6 nephrectomized (5/6 Nx) rat model, to simulate chronic renal failure (CRF) patients, combined with kidney slices and transporter studies in vitro were used to assess this pharmacokinetic differences.

Results

After intragastric administration to 5/6 Nx rats, vildagliptin showed increased plasma levels by 45.8%, and M20.7 by 7.51 times, which was similar to patients with severe renal impairment. The recovery rate of M20.7 in urine and feces increased by less than 20%, showing limited effect of renal impairment on vildagliptin metabolism. In vitro studies found M20.7 to be the substrate for organic anion transporter 3 (OAT3). However, the active uptake of M20.7 in renal slices showed no difference between the 5/6 Nx and normal rats. In OAT3 overexpressed cells, the protein-bound uremic toxins, 3-carboxy-4-methyl-5propyl-2-furanpropionate (CMPF), hippuric acid (HA) and indoxyl sulfate (IS), which accumulate in CRF patients, inhibited M20.7 uptake with IC50 values of 5.75, 29.0 and 69.5 μM respectively, far lower than plasma concentrations in CRF patients, and showed a mixed inhibition type.

Conclusions

The large increase in plasma exposure of M20.7 could be attributed to the accumulation of uremic toxins in CRF patients, which inhibited OAT3 activity and blocked renal excretion of M20.7, while vildagliptin, with high permeability, showed a slight increase in plasma exposure due to reduced glomerular filtration.

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (Grant 82073924). The authors thank Xiao-yan Pang for her assistance with the experiments.

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Author notes

  1. Zitao Guo and Fandi Kong contributed equally to this work.

Authors and Affiliations

  1. School of Environmental Chemistry and Engineering, Shanghai University, 99 Shangda Road BaoShan District, Shanghai, 200444, China

    Zitao Guo & Xiaoyan Chen

  2. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China

    Zitao Guo, Fandi Kong, Ningjie Xie, Zhendong Chen, Jiafeng Hu & Xiaoyan Chen

  3. University of Chinese Academy of Sciences, Beijing, 100049, China

    Fandi Kong, Ningjie Xie, Jiafeng Hu & Xiaoyan Chen

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  1. Zitao Guo
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  2. Fandi Kong
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  3. Ningjie Xie
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Contributions

ZTG, FDK and XYC participated in research design; ZTG, FDK, NJX, ZDC and JFH performed experiments; ZTG and XYC wrote the manuscript.

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Correspondence to Xiaoyan Chen.

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Guo, Z., Kong, F., Xie, N. et al. Mechanistic Study on the Effect of Renal Impairment on the Pharmacokinetics of Vildagliptin and its Carboxylic Acid Metabolite. Pharm Res 39, 2147–2162 (2022). https://doi.org/10.1007/s11095-022-03324-9

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  • DOI: https://doi.org/10.1007/s11095-022-03324-9

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