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

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 IC 50 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.