Mechanism of long-lasting inhibition of transporters as a mechanism of transporter-related drug-drug interactions
Project/Area Number |
21790142
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Research Category |
Grant-in-Aid for Young Scientists (B)
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Allocation Type | Single-year Grants |
Research Field |
Medical pharmacy
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Research Institution | Chiba University |
Principal Investigator |
SHITARA Yoshihisa Chiba University, 大学院・薬学研究院, 准教授 (00306656)
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Project Period (FY) |
2009 – 2010
|
Project Status |
Completed (Fiscal Year 2010)
|
Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2010: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2009: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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Keywords | 薬物動態 / 代謝学 / OATP/Oatp / シクロスポリン / 薬物間相互作用 / 持続的阻害 / 消化管吸収 / 肝取り込み / トランスポーター / OATP / Oatp |
Research Abstract |
Hepatic uptake transporters as well as drug metabolizing enzymes play an important role in elimination of drugs via liver. Among the hepatic transporters, organic anion transporting polypeptides (OATPs/Oatps) are key factors as a determinant of the elimination rates of a number of therapeutic reagents via liver. Thus,, inhibition of hepatic uptake transporters may cause clinically relevant drug-drug interactions (DDIs). We showed that cyclosporine A (CsA) causes a clinically relevant DDI by inhibition of OATPs. In rats, CsA causes a long-lasting inhibition of Oatps. In the present study, we examined the effect of CsA on human OATP1B1 and OATP1B3. CsA has a long-lasting inhibitory effect on the OATP1B1- and OATP1B3-mediaed uptake, with a more potent effect on OATP1B1. However, it caused neither a reduction in the expression level of OATP1B1 nor its altered localization. By using polarized MDCK II cells expressing OATP1B1, it was shown that CsA in the cells caused a long-lasting inhibition of OATP1B1, but its exposure is not required. Thus, also in the clinically relevant DDIs, CsA in the liver may cause a long-lasting inhibition. We also examined the effect of CsA on the intestinal Oatps by using fexofenadine as a model compound in rats. Although CsA increased the intestinal absorption of fexofenadine by inhibiting its intestinal efflux mediated by P-glycoprotein 3 hours after oral administration of CsA, it reduced the intestinal absorption of this drug possibly caused by the inhibition of Oatp-mediated absorption 1 day after the oral administration. Thus, CsA causes a long-lasting inhibition of intestinal Oatps, too.
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Report
(3 results)
Research Products
(14 results)