Coadministration of vindesine with high-dose methotrexate therapy increases acute kidney injury via BCRP, MRP2, and OAT1/OAT3
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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.
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.
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.
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.
KeywordsHigh-dose methotrexate Vindesine Acute kidney injury Transporter-mediated drug interactions Therapeutic drug monitoring
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).
Compliance with ethical standards
Conflict of interest
The authors declare no competing financial interests.
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