Sulindac and its metabolites inhibit multiple transport proteins in rat and human hepatocytes.
Sulindac is a commonly used nonsteroidal anti-inflammatory drug. This study tested the hypothesis that sulindac-mediated drug-drug interactions and/or hepatotoxicity may be caused, in part, by inhibition of proteins responsible for the hepatic transport of drugs and/or bile acids by sulindac and/or sulindac metabolites [sulindac sulfone (S-sulfone) and sulindac sulfide (S-sulfide)]. The uptake and excretion of model substrates, [(3)H]taurocholate (TC), [(3)H]estradiol 17-beta-glucuronide (E217G), and nitrofurantoin (NF), were investigated in rat and human suspended and sandwich-cultured hepatocytes (SCH). In suspended rat hepatocytes, S-sulfone and S-sulfide inhibited Na(+)-dependent TC initial uptake (IC(50) of 24.9 +/- 6.4 and 12.5 +/- 1.8 microM, respectively) and Na(+)-independent E217G initial uptake (IC(50) of 12.1 +/- 1.6 and 6.3 +/- 0.3 microM, respectively). In rat SCH, sulindac metabolites (100 microM) decreased the in vitro biliary clearance (Cl(biliary)) of TC, E217G, and NF by 38 to 83%, 81 to 97%, and 33 to 57%, respectively; S-sulfone and S-sulfide also decreased the TC and NF biliary excretion index by 39 to 55%. In suspended human hepatocytes, S-sulfone and S-sulfide inhibited Na(+)-dependent TC initial uptake (IC(50) of 42.2 and 3.1 microM, respectively); S-sulfide also inhibited the TC Cl(biliary) in human SCH. Sulindac/metabolites markedly inhibited hepatic uptake and biliary excretion of E217G by 51 to 100% in human SCH. In conclusion, sulindac and metabolites are potent inhibitors of the uptake and biliary clearance of bile acids in rat and human hepatocytes and also inhibit substrates of rat breast cancer resistance protein, rat and human organic anion-transporting polypeptides, and human multidrug resistance-associated protein 2. Inhibition of multiple hepatic transport proteins by sulindac/metabolites may play an important role in clinically significant sulindac-mediated drug-drug interactions and/or liver injury.
Lee
Jin Kyung
JK
Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7569, USA.
Paine
Mary F
MF
Brouwer
Kim L R
KL
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors; D009582:Nitrofurantoin / Q000378:metabolism; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors; D051381:Rats; D013467:Sulindac / Q000009:adverse effects / Q000031:analogs & derivatives*; D013656:Taurocholic Acid / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002352:Carrier Proteins; D004958:Estradiol; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009582:Nitrofurantoin; D027361:Organic Anion Transporters; D013467:Sulindac; D013656:Taurocholic Acid; C025483:estradiol-17 beta-glucuronide; C025462:sulindac sulfide; C025463:sulindac sulfone