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Title: In vitro inhibition of OATP-mediated uptake of phalloidin using bile acid derivatives

Hepatocyte uptake of phalloidin is carried out mainly by OATP1B1. We have used this compound as a prototypic substrate and assayed the ability to inhibit OATP-mediated phalloidin transport of four bile acid derivatives (BALU-1, BALU-2, BALU-3 and BALU-4) that showed positive results in preliminary screening. Using Xenopus laevis oocytes for heterologous expression of transporters, BALUs were found to inhibit taurocholic acid (TCA) transport by OATP1B1 (but not OATP1B3) as well as by rat Oatp1a1, Oatp1a4 and Oatp1b2. The study of their ability to inhibit sodium-dependent bile acid transporters revealed that the four BALUs induced an inhibition of rat Asbt-mediated TCA transport, which was similar to TCA-induced self-inhibition. Regarding human NTCP and rat Ntcp, BALU-1 differs from the other three BALUS in its lack of effect on TCA transport by these proteins. Using HPLC-MS/MS and CHO cells stably expressing OATP1B1 the ability of BALU-1 to inhibit the uptake of phalloidin itself by this transporter was confirmed. Kinetic analysis using X. laevis oocytes revealed that BALU-1-induced inhibition of OATP1B1 was mainly due to a competitive mechanism (Ki = 8 {mu}M). In conclusion, BALU-1 may be useful as a pharmacological tool to inhibit the uptake of compounds mainly taken up by OATP1B1 presumablymore » without impairing bile acid uptake by the major carrier accounting for this process, i.e., NTCP.« less
Authors:
;  [1] ;  [2] ; ;  [1] ;  [3]
  1. Laboratory of Experimental Hepatology and Drug Targeting, CIBERehd, University of Salamanca, Salamanca (Spain)
  2. Facultad de Ciencias, Departamento de Quimica Fisica, Campus of Lugo, University of Santiago (Spain)
  3. Laboratory of Experimental Hepatology and Drug Targeting, CIBERehd, University of Salamanca, Salamanca (Spain), E-mail: jjgmarin@usal.es
Publication Date:
OSTI Identifier:
21272622
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 239; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2009.04.024; PII: S0041-008X(09)00204-X; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BILE ACIDS; CARRIERS; ESTRADIOL; HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY; MYCOTOXINS; OOCYTES; POLYPEPTIDES; RATS; TOXICITY