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Coadministration of vindesine with high-dose methotrexate therapy increases acute kidney injury via BCRP, MRP2, and OAT1/OAT3

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Abstract

Purpose

To investigate whether coadministration of vindesine is a risk factor for acute kidney injury caused by high-dose methotrexate in patients with hematologic malignancies and identify its mechanism.

Methods

A retrospective analysis was conducted on 211 cycles of HD-MTX therapy in 178 patients with hematological malignancies. Multivariate logistic regression analysis was performed to evaluate whether VDS coadministration was a risk factor for AKI and the inhibitory effect of VDS on MTX was studied in cell models in vitro.

Results

The occurrence of AKI was significantly higher in the MTX + VDS group than in the MTX group. Multivariate logistic regression analysis showed that VDS coadministration was an important risk factor for the occurrence of AKI [odds ratio (OR) = 2.62, 95% confidence interval (CI) 1.03–6.66]. After coadministration of VDS, serum MTX concentrations at 24 h, 48 h, and 72 h increased from 0.42 ± 0.46 μmol/L, 0.07 ± 0.01 μmol/L, and 0.03 ± 0.01 μmol/L to 0.98 ± 2.73 μmol/L, 0.18 ± 0.42 μmol/L, and 0.09 ± 0.21 μmol/L (p < 0.05, p < 0.01, and p < 0.01), respectively. Delayed elimination was closely related to AKI (p < 0.001). The transfected cell model results showed that VDS is an inhibitor of the transporters BCRP, MRP2, and OAT1/OAT3. VDS inhibited BCRP and MRP2-mediated transport of MTX with IC50 values of 17.91 µM and 34.73 µM, respectively.

Conclusions

Coadministration of VDS increases HD-MTX-induced AKI in patients with hematologic malignancies, which may be explained by the fact that VDS increases the exposure to and decreases the excretion of MTX by inhibiting OAT1/OAT3, BCRP, and MRP2.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (grant number: 81773820), the National Key New Drug Creation Special Programs (2017ZX09304-021), the Jiangsu Provincial Medical Talent (ZDRCA2016048), and the Suzhou Key Laboratory of Drug Clinical Research and Personalized Medicine (SZS201719).

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Author notes

  1. Chenrong Huang and Fan **a contributed equally to this article.

Authors and Affiliations

  1. Department of Clinical Pharmacology, The First Affiliated Hospital of Soochow University, Suzhou, China

    Chenrong Huang, Fan **a, Ling Xue, Linsheng Liu, Yicong Bian & Liyan Miao

  2. Institute for Interdisciplinary Drug Research and Translational Sciences, College of Pharmaceutical Science, Soochow University, Suzhou, China

    Chenrong Huang & Liyan Miao

  3. Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China

    Zhengming **

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  1. Chenrong Huang
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Correspondence to Zhengming ** or Liyan Miao.

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Huang, C., **a, F., Xue, L. et al. Coadministration of vindesine with high-dose methotrexate therapy increases acute kidney injury via BCRP, MRP2, and OAT1/OAT3. Cancer Chemother Pharmacol 85, 433–441 (2020). https://doi.org/10.1007/s00280-019-03972-6

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