Recent advances in understanding hepatic drug transport

Stieger, Bruno; Hagenbuch, Bruno

doi:10.12688/f1000research.9466.1

Cited by 13 publications

(8 citation statements)

References 81 publications

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“…Once in the portal vein, BAs are actively transported into hepatocytes via sodium taurocholate cotransporting polypeptide (NTCP) (Hagenbuch and Meier, 1994) and organic anion-transporting polypeptide (OATP) (Stieger and Hagenbuch, 2016). The remaining BAs enter the colon where bacteria deconjugate and dehydroxylate them to form the main secondary BAs, deoxycholic acid (DCA) and lithocholic acid (LCA).…”

Section: Ba Transportmentioning

confidence: 99%

The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

Chow

Lee

Guo

2017

Molecular Aspects of Medicine

115

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Nonalcoholic fatty liver disease is growing in prevalence worldwide. It is started by the presence of macrosteatosis on liver histology but is often clinically asymptomatic. However, it can progress into nonalcoholic steatohepatitis which is a more severe form of liver disease characterized by inflammation and fibrosis. Further progression leads to cirrhosis, which predisposes patients to hepatocellular carcinoma or liver failure. The mechanism by which simple steatosis progresses to steatohepatitis is not entirely clear. However, multiple pathways have been proposed. A common link amongst many of these pathways is disruption of the homeostasis of bile acids. Other than aiding in the absorption of lipids and lipid-soluble vitamins, bile acids act as ligands. For example, they bind to farnesoid X receptor, which is critically involved in many of the pathways responsible for maintaining bile acid, glucose, and lipid homeostasis. Alterations to these pathways can lead to deregulation in energy balance and increased inflammation and fibrosis. Repeated insults over time may be the key to development of steatohepatitis. For this reason, current drugs target aspects of these pathways to try to reduce and halt inflammation and fibrosis. This review will focus on the role of bile acids in these various pathways and how changes in these pathways may result in steatohepatitis. While there is no approved pharmaceutical treatment for either hepatic steatosis or steatohepatitis, this review will also touch upon the multitude of potential therapies.

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Section: Ba Transportmentioning

confidence: 99%

The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

Chow

Lee

Guo

2017

Molecular Aspects of Medicine

115

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“…17 Comprehensive reviews on substrate specificity, genetics, and mechanism of action of liver transporters have been published in recent years and the reader is referred to these for further details. 12,18 Major Drug Transporters in the Kidney Renal clearance is a major elimination pathway of many drugs, metabolites, and endogenous compounds. The elimination process in the kidney nephron is the net result of glomerular filtration, tubular secretion, and tubular reabsorption.…”

Section: Major Drug Transporters In the Livermentioning

confidence: 99%

Identification of Endogenous Biomarkers to Predict the Propensity of Drug Candidates to Cause Hepatic or Renal Transporter-Mediated Drug-Drug Interactions

Chu

Chan

Evers

2017

Journal of Pharmaceutical Sciences

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Drug transporters expressed in liver and kidney play a critical role in the elimination of a wide range of drugs and xenobiotics and inhibition of these transporters may therefore cause clinically significant drug-drug interactions (DDIs). Currently, in vitro transporter inhibition data are used to assess the risk that a drug candidate may act as an inhibitor of a transporter in patients at clinically relevant exposures. However, this approach is hampered by low confidence in in vitro to in vivo extrapolations, and large inter-system and inter-laboratory variability in in vitro data. Several endogenous compounds have been identified as substrates of drug transporters. Determining the impact of perpetrator drugs on the plasma or urinary exposure of these potential endogenous biomarkers in humans is being explored as an alternative approach to assess the DDI liability of drug candidates, especially in early drug development. In this review, we provide an overview of recently identified biomarkers used to study the inhibition of hepatic and renal transporters; summarize the methods and strategies employed to identify biomarkers; and discuss the utility, limitation, and future direction of biomarker approaches to predict transporter-mediated DDIs.

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“…Solute carrier transporters are crucial for an active vectorial BA uptake 1, 2. Among these, the sodium taurocholate cotransporter polypeptide (NTCP; SLC10A1) is a major BA uptake transporter in the liver that preferentially moves conjugated BA into mature hepatocytes in a sodium‐dependent manner 3, 4, 5.…”

mentioning

confidence: 99%

Age‐dependent glycosylation of the sodium taurocholate cotransporter polypeptide: From fetal to adult human livers

Sargiacomo

El-Kehdy

Pourcher

et al. 2018

Hepatology Communications

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Sodium taurocholate cotransporter polypeptide (NTCP), mainly expressed on the sinusoidal membrane of hepatocytes, is one of the major transporters responsible for liver bile acid (BA) re‐uptake. NTCP transports conjugated BA from the blood into hepatocytes and is crucial for correct enterohepatic circulation. Studies have shown that insufficient hepatic clearance of BA correlates with elevated serum BA in infants younger than 1 year of age. In the current study, we investigated human NTCP messenger RNA and protein expression by using reverse‐transcription quantitative polymerase chain reaction and immunoblotting in isolated and cryopreserved human hepatocytes from two different age groups, below and above 1 year of age. Here, we show that NTCP messenger RNA expression is not modulated whereas NTCP protein posttranslational glycosylation is modulated in an age‐dependent manner. These results were confirmed by quantification analysis of NTCP 55‐kDa N‐glycosylated bands, which showed significantly less total NTCP protein in donors below 1 year of age compared to donors older than 1 year. NTCP tissue localization was also analyzed by means of immunofluorescence. This revealed that NTCP cellular localization in fetal samples was mainly perinuclear, suggesting that NTCP is not glycosylated, while its postnatal localization on the plasma membrane is age dependent compared to multidrug resistant protein 2, which is apical starting in fetal life. Conclusion: After birth, the NTCP age‐dependent maturation process requires approximately 1 year to complete NTCP glycosylation in human hepatocytes. Therefore, NTCP late posttranslational glycosylation appears to be important for correct NTCP membrane localization, which might explain physiologic cholestasis in neonatal life and might play a central role for HBV infection after birth. (Hepatology Communications 2018;2:693‐702)

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Recent advances in understanding hepatic drug transport

Cited by 13 publications

References 81 publications

The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

Identification of Endogenous Biomarkers to Predict the Propensity of Drug Candidates to Cause Hepatic or Renal Transporter-Mediated Drug-Drug Interactions

Age‐dependent glycosylation of the sodium taurocholate cotransporter polypeptide: From fetal to adult human livers

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