Abstract
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, [3H]taurocholate (TC), [3H]estradiol 17-β-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 (IC50 of 24.9 ± 6.4 and 12.5 ± 1.8 μM, respectively) and Na+-independent E217G initial uptake (IC50 of 12.1 ± 1.6 and 6.3 ± 0.3 μM, respectively). In rat SCH, sulindac metabolites (100 μM) decreased the in vitro biliary clearance (Clbiliary) 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 (IC50 of 42.2 and 3.1 μM, respectively); S-sulfide also inhibited the TC Clbiliary 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.
Footnotes
This work was supported by the National Institutes of Health [Grant R01-GM41935] and pilot funding by the North Carolina Translational and Clinical Sciences Institute provided by the National Institutes of Health National Center for Research Resources, [Award UL1RR025747].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.165852.
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ABBREVIATIONS:
- S-sulfone
- sulindac sulfone
- S-sulfide
- sulindac sulfide
- NSAID
- nonsteroidal anti-inflammatory drug
- TC
- taurocholate
- E217G
- estradiol 17-|gb-glucuronide
- NF
- nitrofurantoin
- SCH
- sandwich-cultured hepatocytes
- BSEP
- bile salt export pump
- NTCP
- Na+-dependent taurocholate cotransporting polypeptide
- OAT
- organic anion transporter
- OATP
- organic anion-transporting polypeptide
- MRP
- multidrug resistance-associated protein
- DILI
- drug-induced liver injury
- BEI
- biliary excretion index
- ANOVA
- analysis of variance
- HBSS
- Hanks' balanced salt solution
- DMEM
- Dulbecco's modified Eagle's medium
- AUC
- area under the concentration-time curve
- BCRP
- breast cancer resistance protein
- Clbiliary
- biliary clearance
- HPLC
- high-performance liquid chromatography
- MS/MS
- tandem mass spectroscopy
- Cmax
- peak plasma total concentration.
- Received January 11, 2010.
- Accepted April 28, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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