HepaRG human hepatic cell line utility as a surrogate for primary human hepatocytes in drug metabolism assessment in vitro

Lübberstedt, Marc; Müller‐Vieira, Ursula; Mayer, Manuela; Biemel, Klaus M.; Knöspel, Fanny; Knobeloch, Daniel; Nüssler, Andreas K.; Gerlach, Jörg C.; Zeilinger, Katrin

doi:10.1016/j.vascn.2010.04.013

Cited by 192 publications

(132 citation statements)

References 35 publications

Supporting

Mentioning

122

Contrasting

Order By: Relevance

“…The underprediction for CYP2D6 metabolized compounds in HepaRG™ has already been reported due to a CYP2D6-deficient donor (11,30,31). However, the fold of underprediction seems to vary between the applied enzyme markers due to potential metabolism by multiple CYP enzymes (11,(30)(31)(32). For example, the intrinsic clearances in HepaRG™ as compared to suspension cultures were decreased more for dextromethorphan and metoprolol than for propranolol (11,30).…”

Section: Metabolic Activity Assessment Of In Vitro Liver Models and Cmentioning

confidence: 83%

“…However, pronounced differences in metabolic activities were observed for CYP2D6. The underprediction for CYP2D6 metabolized compounds in HepaRG™ has already been reported due to a CYP2D6-deficient donor (11,30,31). However, the fold of underprediction seems to vary between the applied enzyme markers due to potential metabolism by multiple CYP enzymes (11,(30)(31)(32).…”

Section: Metabolic Activity Assessment Of In Vitro Liver Models and Cmentioning

confidence: 88%

See 1 more Smart Citation

Metabolic Profiling of Human Long-Term Liver Models and Hepatic Clearance Predictions from In Vitro Data Using Nonlinear Mixed-Effects Modeling

Kratochwil

Meille

Fowler

et al. 2017

AAPS J

View full text Add to dashboard Cite

ABSTRACT.Early prediction of human clearance is often challenging, in particular for the growing number of low-clearance compounds. Long-term in vitro models have been developed which enable sophisticated hepatic drug disposition studies and improved clearance predictions. Here, the cell line HepG2, iPSC-derived hepatocytes (iCell®), the hepatic stem cell line HepaRG™, and human hepatocyte co-cultures (HμREL™ and HepatoPac®) were compared to primary hepatocyte suspension cultures with respect to their key metabolic activities. Similar metabolic activities were found for the long-term models HepaRG™, HμREL™, and HepatoPac® and the short-term suspension cultures when averaged across all 11 enzyme markers, although differences were seen in the activities of CYP2D6 and non-CYP enzymes. For iCell® and HepG2, the metabolic activity was more than tenfold lower. The micropatterned HepatoPac® model was further evaluated with respect to clearance prediction. To assess the in vitro parameters, pharmacokinetic modeling was applied. The determination of intrinsic clearance by nonlinear mixed-effects modeling in a long-term model significantly increased the confidence in the parameter estimation and extended the sensitive range towards 3% of liver blood flow, i.e., >10-fold lower as compared to suspension cultures. For in vitro to in vivo extrapolation, the well-stirred model was used. The micropatterned model gave rise to clearance prediction in man within a twofold error for the majority of low-clearance compounds. Further research is needed to understand whether transporter activity and drug metabolism by non-CYP enzymes, such as UGTs, SULTs, AO, and FMO, is comparable to the in vivo situation in these long-term culture models.KEY WORDS: in vitro clearance; in vitro liver models; IVIVE; nonlinear mixed-effects modeling.

show abstract

Section: Metabolic Activity Assessment Of In Vitro Liver Models and Cmentioning

confidence: 83%

Section: Metabolic Activity Assessment Of In Vitro Liver Models and Cmentioning

confidence: 88%

Metabolic Profiling of Human Long-Term Liver Models and Hepatic Clearance Predictions from In Vitro Data Using Nonlinear Mixed-Effects Modeling

Kratochwil

Meille

Fowler

et al. 2017

AAPS J

View full text Add to dashboard Cite

show abstract

“…These cells, when plated at low density with medium containing DMSO, differentiate into two cell types, resembling either adult primary hepatocytes (with bile canaliculi) or biliary epithelial cells (Parent et al, 2004) and are able to perform many specific liver functions and respond to prototypical drug metabolism inducers. Moreover, modulation of the concentration of DMSO during the differentiation process can result in expression of cytochrome P450 and transporters at levels similar to or greater than those in primary human hepatocytes in culture (Aninat et al, 2006;Lübberstedt et al, 2011). Since becoming available, HepaRG cells have been used successfully for assessment of cytochrome P450 induction (McGinnity et al, 2009;Anthérieu et al, 2010) and in toxicology studies (Dumont et al, 2010;Lübberstedt et al, 2011;McGill et al, 2011) and appear to have the potential for further understanding of the interplay between drug metabolism, cell metabolism, and liver function in preclinical toxicological studies for either known drugs and new chemical entities.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, modulation of the concentration of DMSO during the differentiation process can result in expression of cytochrome P450 and transporters at levels similar to or greater than those in primary human hepatocytes in culture (Aninat et al, 2006;Lübberstedt et al, 2011). Since becoming available, HepaRG cells have been used successfully for assessment of cytochrome P450 induction (McGinnity et al, 2009;Anthérieu et al, 2010) and in toxicology studies (Dumont et al, 2010;Lübberstedt et al, 2011;McGill et al, 2011) and appear to have the potential for further understanding of the interplay between drug metabolism, cell metabolism, and liver function in preclinical toxicological studies for either known drugs and new chemical entities. Kanebratt and Andersson (2008) have demonstrated activities of several major drug-metabolizing cytochrome P450s in cultured HepaRG cells, which were of a magnitude similar to that in primary hepatocytes.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Cryopreserved HepaRG Cells with Cryopreserved Human Hepatocytes for Prediction of Clearance for 26 Drugs

Zanelli¹,

Caradonna²,

Hallifax³

et al. 2011

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Prediction of clearance in drug discovery currently relies on human primary hepatocytes, which can vary widely in drug-metabolizing enzyme activity. Potential alternative in vitro models include the HepaRG cell (from immortalized hepatoma cells), which in culture can express drug-metabolizing enzymes to an extent comparable to that of primary hepatocytes. Utility of the HepaRG cell will depend on robust performance, relative to that of primary hepatocytes, in routine high-throughput analysis. In this study, we compared intrinsic clearance (CL int ) in the recently developed cryopreserved HepaRG cell system with CL int in human cryopreserved pooled hepatocytes and with CL int in vivo for 26 cytochrome P450 substrate drugs. There was quantitative agreement between CL int in HepaRG cells and human hepatocytes, which was linear throughout the range of CL int (1-2000 ml ⅐ min ؊1 ⅐ kg ؊1 ) and not dependent on particular cytochrome P450 involvement. Prediction of CL int in HepaRG cells was on average within 2-fold of in vivo CL int (using the well stirred liver model), but average fold error was clearance-dependent with greater underprediction (up to at least 5-fold) for the more highly cleared drugs. Recent reporting of this phenomenon in human hepatocytes was therefore confirmed with the hepatocytes used in this study, and hence the HepaRG cell system appears to share an apparently general tendency of clearance-limited CL int in cell models. This study shows the cryopreserved HepaRG cell system to be quantitatively comparable to human hepatocytes for prediction of clearance of drug cytochrome P450 substrates and to represent a promising alternative in vitro tool.

show abstract

“…It is worth noting that the level of automated parameter control, such as in-process controls of pH and pO 2 , of the chip-based liver equivalents reviewed here do not compare with the advanced macroscale bioartificial liver-assist systems used at the patient's bedside, and the corresponding hollow fibrebased research liver bioreactor system of Zeilinger and colleagues. 77,78 With regard to the commercial element, throughput and costs, the features listed in Table 3 highlight two obvious facts: (i) The liver equivalent number operated by the devices reported is far from being compliant with high throughput requirements, and (ii) ensuring circulating fluid flow in liver equivalents requires pump systems with control units attached. Any such addition of technical equipment to operate the chip-based liver equivalents, limits their throughput capacity at increasing costs per single test point.…”

Section: Complex Organotypicalness Versus Cost-efficient Throughputmentioning

confidence: 99%

Chip-based liver equivalents for toxicity testing – organotypicalness versus cost-efficient high throughput

2013

View full text Add to dashboard Cite

Drug-induced liver toxicity dominates the reasons for pharmaceutical product ban, withdrawal or nonapproval since the thalidomide disaster in the late-1950s. Hopes to finally solve the liver toxicity test dilemma have recently risen to a historic level based on the latest progress in human microfluidic tissue culture devices. Chip-based human liver equivalents are envisaged to identify liver toxic agents regularly undiscovered by current test procedures at industrial throughput. In this review, we focus on advanced microfluidic microscale liver equivalents, appraising them against the level of architectural and, consequently, functional identity with their human counterpart in vivo. We emphasise the inherent relationship between human liver architecture and its drug-induced injury. Furthermore, we plot the current socio-economic drug development environment against the possible value such systems may add.Finally, we try to sketch a forecast for translational innovations in the field.

show abstract

HepaRG human hepatic cell line utility as a surrogate for primary human hepatocytes in drug metabolism assessment in vitro

Cited by 192 publications

References 35 publications

Metabolic Profiling of Human Long-Term Liver Models and Hepatic Clearance Predictions from In Vitro Data Using Nonlinear Mixed-Effects Modeling

Metabolic Profiling of Human Long-Term Liver Models and Hepatic Clearance Predictions from In Vitro Data Using Nonlinear Mixed-Effects Modeling

Comparison of Cryopreserved HepaRG Cells with Cryopreserved Human Hepatocytes for Prediction of Clearance for 26 Drugs

Chip-based liver equivalents for toxicity testing – organotypicalness versus cost-efficient high throughput

Contact Info

Product

Resources

About