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• W2804785564 abstract "1. Oatp inhibitors have been shown to significantly increase the plasma exposure of statins. However, understanding alterations of liver concentration is also important. While modeling has simulated liver concentration changes, availability of experimental data is limited, especially when concerning drug-drug interactions (DDI). The objective of this work was to determine blood and liver concentrations of fluvastatin, lovastatin and pitavastatin, when blocking uptake transporters. 2. In wild-type mouse, rifampin pre-treatment decreased the unbound liver-to-plasma ratio (Kp,uu) of fluvastatin by 4.2-fold to 2.2, lovastatin by 4.9-fold to 0.81 and pitavastatin by 10-fold to 0.21. Changes in Kp,uu were driven by increases in systemic exposures as liver concentrations were not greatly altered. 3. In Oatp1a/1b knockout mouse (KO), rifampin exerted no additional effect on fluvastatin and lovastatin. Contrarily, rifampin further decreased pitavastatin Kp,uu by 3.4-fold, suggesting that the KO is inadequate to completely block liver uptake of pitavastatin as there are additional rifampin-sensitive uptake mechanism(s) not captured in the KO model. 4. This work provides experimental data showing that the plasma compartment is more sensitive to Oatp modulation than the liver compartment, even for rifampin-mediated DDI. Consistent with previous simulations, inhibiting or targeting Oatps may change Kp,uu, but exhibit only a minimal effect on absolute liver concentrations." @default.
• W2804785564 created "2018-06-01" @default.
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• W2804785564 date "2018-06-06" @default.
• W2804785564 modified "2023-09-26" @default.
• W2804785564 title "Unremarkable impact of Oatp inhibition on the liver concentration of fluvastatin, lovastatin and pitavastatin in wild-type and Oatp1a/1b knockout mouse" @default.
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• W2804785564 doi "https://doi.org/10.1080/00498254.2018.1478167" @default.
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