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• W2945736670 abstract "Organic anion transporting polypeptide 2B1 (OATP2B1) is a widely expressed membrane transporter with diverse substrate specificity. In vitro and clinical studies suggest a role for intestinal OATP2B1 in the oral absorption of medications. Moreover, OATP2B1 is highly expressed in hepatocytes where it is thought to promote liver drug clearance. However, until now, a shortcoming of studies implicating OATP2B1 in drug disposition has been a lack of in vivo models. Here, we report the development of a knockout (KO) mouse model with targeted, global disruption of the <i>Slco2b1</i> gene to examine the disposition of two confirmed mOATP2B1 substrates, namely, fexofenadine and rosuvastatin. The plasma pharmacokinetics of intravenously administered fexofenadine was not different between KO and wild-type (WT) mice. However, after oral fexofenadine administration, KO mice had 70% and 41% lower maximal plasma concentration (<i>C</i>_max) and area under the plasma concentration-time curve (AUC_0–last) than WT mice, respectively. In WT mice, coadministration of fexofenadine with grapefruit juice (GFJ) or apple juice (AJ) was associated with reduced <i>C</i>_max by 80% and 88%, respectively, while the AUC_0–last values were lower by 35% and 70%, respectively. In KO mice, AJ coadministration reduced oral fexofenadine <i>C</i>_max and AUC_0–last values by 67% and 59%, respectively, while GFJ had no effects. Intravenous and oral rosuvastatin pharmacokinetics were similar among WT and KO mice. We conclude that intestinal OATP2B1 is a determinant of oral fexofenadine absorption, as well as a target for fruit juice interactions. OATP2B1 does not significantly influence rosuvastatin disposition in mice. <h3>Significance Statement</h3> A novel mouse model with targeted disruption of the <i>Slco2b1</i> gene revealed that OATP2B1 is a determinant of oral absorption but not systemic disposition of fexofenadine, as well as a target of fruit juice interactions. Rosuvastatin oral and intravenous pharmacokinetics were not dependent on OATP2B1. These findings support the utility of the <i>Slco2b1</i> KO mouse model for defining mechanisms of drug disposition at the intersection of in vitro and clinical pharmacology." @default.
• W2945736670 created "2019-05-29" @default.
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• W2945736670 date "2019-05-23" @default.
• W2945736670 modified "2023-10-09" @default.
• W2945736670 title "Fexofenadine and Rosuvastatin Pharmacokinetics in Mice with Targeted Disruption of Organic Anion Transporting Polypeptide 2B1" @default.
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• W2945736670 doi "https://doi.org/10.1124/dmd.119.087619" @default.
• W2945736670 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31123035" @default.
• W2945736670 hasPublicationYear "2019" @default.
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