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

Abstract

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 24h, 48h, and 72h increased from 0.42 ± 0.46μmol/L, 0.07 ± 0.01μmol/L, and 0.03 ± 0.01μmol/L to 0.98 ± 2.73μmol/L, 0.18 ± 0.42μmol/L, and 0.09 ± 0.21μmol/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 17.91µM and 34.73µM, 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.