Inhibitory mechanisms of hepatic uptake transporters/OATP during renal failure

2015 Fiscal Year Final Research Report

• Project/Area Number: 26860099
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: Kanazawa University
• Principal Investigator: MASUO YUSUKE 金沢大学, 薬学系, 助教 (90708140)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: トランスポーター / 慢性腎障害 / 尿毒素

Outline of Final Research Achievements

Several uremic toxins have been proposed to inhibit hepatic uptake transporters. The purpose is to clarify possible long-lasting inhibition of OATP1B1 by uremic toxins. OATP1B1-mediated uptake of [3H]estrone sulfate (E3S) was examined after co-incubation or preincubation with uremic toxins in HEK293/OATP1B1 cells and primary cultured human hepatocytes. Among 21 uremic toxins, indoxyl sulfate (IS), CMPF and p-cresyl sulfate directly inhibited OATP1B1 mediated-uptake of E3S, but only IS exhibited inhibitory effect even after preincubation. Such inhibition of E3S uptake by preincubation with IS was more remarkable than that by its co-incubation, and observed in preincubation time- and concentration-dependent manners. Preincubation with IS also decreased uptake of E3S in human hepatocytes in primary culture. Overall, the long-lasting inhibition in the presence of IS could at least partially explain the delayed elimination of OATP1B1 substrate drugs during severe renal failure.

Free Research Field

薬物治療学