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Losartan is a Substrate of Organic Anion Transporting Polypeptide 2B1
Author(s) -
Flynn Colleen Ann,
Hagenbuch Bruno A.,
Reed Gregory A.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.758.2
Subject(s) - losartan , chemistry , organic anion transporting polypeptide , organic anion , transporter , substrate (aquarium) , cyp2c9 , angiotensin ii , pharmacology , biochemistry , receptor , ion , enzyme , biology , organic chemistry , ecology , cytochrome p450 , gene
Losartan, an angiotensin II receptor antagonist, is used as a probe of CYP2C9 activity both alone and in probe drug cocktails. Although losartan conversion to E3174 provides an index of CYP2C9 activity, transporters may also play a role in losartan disposition. Therefore, we tested whether losartan would affect organic anion transporting polypeptide (OATP) 2B1‐mediated transport. Uptake ofthe model substrate estrone‐3‐sulfate (E3S) was measured using a CHOcell line stably expressing OATP2B1 in theabsence and presence of losartan at pH 7.4 and pH 5.5. OATP2B1‐mediated uptake of E3S was strongly inhibited by losartan at both pHs, with IC 50 values of 8.2 μM at pH 7.4 and 2.8 μM at pH 5.5, indicating that losartan could be a substrate of OATP2B1. To test this, losartan transport was measured at pH 5.5 and 7.4. Uptake was higher at pH 5.5 as compared to pH 7.4 and initial kinetics at pH 7.4 showed saturable uptake (K m = 16.6 μM). These resultsdemonstrate that losartan is a novel substrate of OATP2B1 at both pH 7.4 and 5.5, with increased transport capacity at the lower pH. We are currently characterizing the OATP2B1‐mediated losartan transport and will also examine this transporter as a site for drug‐drug interactions.