Screening of OATP1B1/3 and OCT1 inhibitors in cryopreserved hepatocytes in suspension

Lassina Badolo, Louise Munk Rasmussen, Helle Rusz Hansen, Christina Sveigaard

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33 Citations (Scopus)


Drug-drug interactions involving hepatic drug transporters may have clinical consequences and jeopardize development of promising drug candidates. Organic anion transporting polypeptides (OATP/Oatp) and the organic cation transporters (OCT/Oct) are among the most important transporters involved in xenobiotic uptake in the liver. In the present study, 179 molecules have been tested as inhibitors of the uptake of estradiol-17 beta D-glucuronide (E(2)17 beta G), substrate of OATP1B1/3 (rOatp), or 1-methyl-4-phenylpyridinium (MPP+), substrate of OCT1 (rOct1), into suspended cryopreserved hepatocytes from humans and rats. Uptake was assessed in 96-well plates by measuring intracellular accumulation of radioactive substrate in hepatocytes in presence or absence of inhibitor.

In rat hepatocytes 140 compounds were identified as inhibitors (inhibition at 20 mu M >= 30%) of E(2)17 beta G uptake and 77 compounds inhibitors of MPP+ uptake. The most potent inhibitors of rOatp and rOct1 were dantrolene sodium (K-i = 2 +/- 9 mu M) and bepridil (K-i =14 +/- 2 mu M), respectively. In human hepatocytes, the most potent inhibitors of E(2)17 beta G and MPP+ uptake were capsazepine(K-i = 14 +/- 5 mu M) and cyproheptadine (K-i = 19 +/- 3 mu M), respectively.

Structure-activity relationship (SAR) analysis of all tested compounds suggested that lipophilicity, polarity, pK(a) and the number of hydrogen bond donors and acceptors play a role in their interaction with the transporters investigated.

The method used here is a simple tool to screen large number of compounds as inhibitors of the uptake of substrates into suspended hepatocytes. (c) 2010 Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)282-288
Number of pages7
JournalEuropean Journal of Pharmaceutical Sciences
Issue number4
Publication statusPublished - 11 Jul 2010


  • Hepatocytes
  • Transporters
  • Inhibition
  • OATP
  • OCT1
  • Screening
  • organic cation transporters
  • hepatic-uptake
  • fexofenadine
  • clearance


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