Hepatocellular Exposure of Troglitazone Metabolites in Rat Sandwich-Cultured Hepatocytes Lacking Bcrp and Mrp2: Interplay between Formation and Excretion

Yang, Kunlun; Brouwer, Kim L. R.

doi:10.1124/dmd.114.057190

Cited by 7 publications

(2 citation statements)

References 49 publications

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“…49 The interplay between formation and excretion of TGZ metabolites was studied in rat SCH lacking Bcrp and Mrp2 by Yang et al using RNA interference techniques to knock down Bcrp in SCH prepared from TR − rats. 58 In some cases, only the metabolites are transporter inhibitors. For example, although estradiol and bilirubin do not inhibit MRP2, pre-exposure of rat SCH to estradiol and bilirubin decreased the biliary excretion of 5-(and 6)-carboxy-2′,7′-dichlorofluorescein, a MRP2 substrate, which could be attributed to the inhibition by the generated metabolites of estradiol and bilirubin.…”

Section: Use Of Sandwich–cultured Hepatocytes In Studying Drug Disposmentioning

confidence: 99%

Sandwich-Cultured Hepatocytes as a Tool to Study Drug Disposition and Drug-Induced Liver Injury

Yang

Guo

Woodhead

et al. 2016

Journal of Pharmaceutical Sciences

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Sandwich-cultured hepatocytes (SCH) are metabolically competent and have proper localization of basolateral and canalicular transporters with functional bile networks. Therefore, this cellular model is a unique tool that can be used to estimate biliary excretion of compounds. SCH have been used widely to assess hepatobiliary disposition of endogenous and exogenous compounds and metabolites. Mechanistic modeling based on SCH data enables estimation of metabolic and transporter-mediated clearances, which can be employed to construct physiologically-based pharmacokinetic models for prediction of drug disposition and drug-drug interactions in humans. In addition to pharmacokinetic studies, SCH also have been employed to study cytotoxicity and perturbation of biological processes by drugs and hepatically-generated metabolites. Human SCH can provide mechanistic insights underlying clinical drug-induced liver injury (DILI). In addition, data generated in SCH can be integrated into systems pharmacology models to predict potential DILI in humans. In this review, applications of SCH in studying hepatobiliary drug disposition and bile acid-mediated DILI are discussed. An example is presented to show how data generated in the SCH model was used to establish a quantitative relationship between intracellular bile acids and cytotoxicity, and how this information was incorporated into a systems pharmacology model for DILI prediction.

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Section: Use Of Sandwich–cultured Hepatocytes In Studying Drug Disposmentioning

confidence: 99%

Sandwich-Cultured Hepatocytes as a Tool to Study Drug Disposition and Drug-Induced Liver Injury

Yang

Guo

Woodhead

et al. 2016

Journal of Pharmaceutical Sciences

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“…It was suggested that both a compound’s susceptibility to glucuronidation by the UGT enzyme and the resulting glucuronide’s affinity to efflux transporter determined a compound’s susceptibility to glucuronidation in cells (63). Rat SCH lacking Bcrp (using adenoviral vectors expressing shRNA targeting Bcrp) and/or Mrp2 (from Mrp2-knockout rat) was also used previously to study the interplay between the formation of a glucuronide and its excretion by specific transporter (s) (108). …”

Section: Mechanistic Modeling Of Glucuronide Dispositionmentioning

confidence: 99%

Challenges and Opportunities with Predicting In Vivo Phase II Metabolism via Glucuronidation From In Vitro Data

2016

Curr Pharmacol Rep

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Glucuronidation is the most important phase II metabolic pathway which is responsible for the clearance of many endogenous and exogenous compounds. To better understand the elimination process for compounds undergoing glucuronidation and identify compounds with desirable in vivo pharmacokinetic properties, many efforts have been made to predict in vivo glucuronidation using in vitro data. In this article, we reviewed typical approaches used in previous predictions. The problems and challenges in prediction of glucuronidation were discussed. Besides that different incubation conditions can affect the prediction accuracy, other factors including efflux / uptake transporters, enterohepatic recycling, and deglucuronidation reactions also contribute to the disposition of glucuronides and make the prediction more difficult. PBPK modeling, which can describe more complicated process in vivo, is a promising prediction strategy which may greatly improve the prediction of glucuronidation and potential DDIs involving glucuronidation. Based on previous studies, we proposed a transport-glucuronidation classification system, which was built based on the kinetics of both glucuronidation and transport of the glucuronide. This system could be a very useful tool to achieve better in vivo predictions.

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In vitro drug metabolism and pharmacokinetics of a novel thiazolidinedione derivative, a potential anticancer compound

Shankar

Vuppu

2020

Journal of Pharmaceutical and Biomedical Analysis

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Hepatocellular Exposure of Troglitazone Metabolites in Rat Sandwich-Cultured Hepatocytes Lacking Bcrp and Mrp2: Interplay between Formation and Excretion

Cited by 7 publications

References 49 publications

Sandwich-Cultured Hepatocytes as a Tool to Study Drug Disposition and Drug-Induced Liver Injury

Sandwich-Cultured Hepatocytes as a Tool to Study Drug Disposition and Drug-Induced Liver Injury

Challenges and Opportunities with Predicting In Vivo Phase II Metabolism via Glucuronidation From In Vitro Data

In vitro drug metabolism and pharmacokinetics of a novel thiazolidinedione derivative, a potential anticancer compound

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