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Eur J Pharm Sci. 2010 Jul 11;40(4):282-8. doi: 10.1016/j.ejps.2010.03.023. Epub 2010 Apr 8.

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

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Department of Discovery ADME, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.


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-17betaD-glucuronide (E(2)17betaG), 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 microM > or = 30%) of E(2)17betaG uptake and 77 compounds inhibitors of MPP+ uptake. The most potent inhibitors of rOatp and rOct1 were dantrolene sodium (K(i)=2 +/- 9 microM) and bepridil (K(i)=14 +/- 2 microM), respectively. In human hepatocytes, the most potent inhibitors of E(2)17betaG and MPP+ uptake were capsazepine (K(i)=14 +/- 5 microM) and cyproheptadine (K(i)=19+/-3 microM), 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.

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