ArticleDrug metabolism and disposition: the biological fate of chemicals2014
Hepatocellular exposure of troglitazone metabolites in rat sandwich-cultured hepatocytes lacking Bcrp and Mrp2: interplay between formation and excretion.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed, 7 citations in OpenAlex.
- High-throughput human microfluidic organoid-on-a-chip platform for modeling liver diseases and screening nanotherapeutics.Journal of nanobiotechnology · 2026Article
- Challenges and Opportunities with Predicting in Vivo Phase II Metabolism via Glucuronidation from in Vitro Data.Current pharmacology reports · 2016Article
- Sandwich-Cultured Hepatocytes as a Tool to Study Drug Disposition and Drug-Induced Liver Injury.Journal of pharmaceutical sciences · 2016Review
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2 authors at 1 institution in 1 country.
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Abstract
Inhibition of bile acid transport by troglitazone (TGZ) and its major metabolite, TGZ sulfate (TS), may lead to hepatocellular accumulation of toxic bile acids; TS accumulation and hepatotoxicity may be associated with impaired TS biliary excretion. This study evaluated the impact of impaired transport of breast cancer resistance protein (Bcrp) and multidrug resistance-associated protein 2 (Mrp2) on the hepatobiliary disposition of generated metabolites, TS and TGZ glucuronide (TG). Sandwich-cultured hepatocytes (SCH) from Mrp2-deficient (TR(-)) rats in combination with Bcrp knockdown using RNA interference were employed. The biliary excretion index (BEI) of generated TS was not significantly altered by impaired Bcrp (20.9 to 21.1%) and/or Mrp2 function (24.4% and 17.5% in WT and TR(-) rat SCH, respectively). Thus, loss-of-function of Mrp2 and/or Bcrp do not appear to be risk factors for increased hepatocellular TS accumulation in rats, potentially because of a compensatory transporter(s) that excretes TS into bile. Further investigations revealed that the compensatory TS biliary transporter was not the bile salt export pump (Bsep) or P-glycoprotein (P-gp). Interestingly, TGZ sulfation was significantly decreased in TR(-) compared with WT rat SCH (total recovery: 2.8 versus 5.0% of TGZ dose), resulting in decreased hepatocellular TS accumulation, even though sulfotransferase activity in TR(-) rat hepatocyte S9 fraction was similar. Hepatocellular TG accumulation was significantly increased in TR(-) compared with WT rat SCH due to increased glucuronidation and negligible TG biliary excretion. These data emphasize that the interplay between metabolite formation and excretion determines hepatocellular exposure to generated metabolites such as TS and TG.
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