2010 Fiscal Year Final Research Report
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 |
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| Research Field |
Medical pharmacy
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| Research Institution | Chiba University |
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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
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| Keywords | 薬物動態 / 代謝学 |
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| 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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