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- W2746714025 abstract "Vincristine is known to interfere with OATP-mediated uptake of other compounds, hinting that vincristine itself could be a substrate of OATP transporters. The present study therefore aimed to investigate the role of OATP transporters in the hepatocellular disposition of vincristine. Vincristine uptake was studied in suspended rat and human hepatocytes as well as OATP-transfected Chinese hamster ovary (CHO) cells in the absence and presence of OATP transporter inhibitors. Membrane vesicles containing MDR1 or MRP1/2/3 were used to directly assess the role of these efflux transporters in vincristine disposition. Uptake in suspended rat hepatocytes was temperature-dependent and could be inhibited by a range of OATP inhibitors. Furthermore, the MRP-inhibitor benzbromarone, but none of the tested MDR1 inhibitors, reduced vincristine efflux in rat and human suspended hepatocytes. OATP1B1-, OATP1B3- and OATP2B1- transfected CHO cells showed significantly increased vincristine uptake as compared to wild-type cells. Moreover, uptake in OATP-transfected CHO cells was reduced by OATP inhibitors. However, uptake studies in suspended human hepatocytes showed that only 10% of the total vincristine uptake process could be attributed to OATP-mediated transport. Studies with transporter-expressing membrane vesicles confirmed vincristine as an MDR1 substrate, while MRP1/2/3-mediated transport of vincristine could not be observed with this model system. Our findings show the involvement of OATP transporters in the disposition of vincristine in rat and human hepatocytes. However, in both species, hepatic uptake is overshadowed by a benzbromarone-sensitive efflux mechanism, possibly MRP3." @default.
- W2746714025 created "2017-08-31" @default.
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- W2746714025 date "2017-08-21" @default.
- W2746714025 modified "2023-09-28" @default.
- W2746714025 title "Role of the OATP Transporter Family and a Benzbromarone-SensitiveEfflux Transporter in the Hepatocellular Disposition of Vincristine" @default.
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- W2746714025 doi "https://doi.org/10.1007/s11095-017-2241-0" @default.
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