A unique in vitro system for ADME/Tox studies
HepaRG™ cells are terminally differentiated hepatic cells derived from a human hepatic progenitor cell line that retains many characteristics of primary human hepatocytes. HepaRG™ cells are provided in a convenient cryopreserved, single use format. For scientists who need reproducible metabolism data, HepaRG™ cells are an in vitro tool that provides reproducible results in a metabolically complete and scalable system.
HepaRG™ cells exhibit many characteristics of primary human hepatocytes, including morphology and expression of key metabolic enzymes, nuclear receptors, and drug transporters. Unlike HepG2 and Fa2N-4 cells, HepaRG™ cells have high P450 activity and complete expression of all nuclear receptors.
HepaRG™ cells lack donor variability, and lot sizes are not limited by donor tissue availability, ensuring an indefinite and consistent supply of cells. Thus experimental results can be infinitely reproduced. （注： The cells provided by Life Technologies are terminally differentiated and cryopreserved.)
P450 enzymes can be induced as a result of drug exposure, which may cause increased formation of toxic metabolites and/or decreased systemic levels of a co-administered drug potentially resulting in drug toxicity or decreased drug efficacy. The use of primary human hepatocytes in screening applications is limited by tissue availability, donor variability, cost, and a relative short culture lifespan. The use of HepaRG™ cells solves these limitations without sacrificing critical hepatocyte traits such as drug metabolizing enzyme expression, functional transport proteins, and expression of key nuclear receptor pathways. HepaRG™ cells respond to prototypical P450 inducers such as omeprazole (OMP), phenobarbital (PB), and rifampicin (RIF) demonstrating the utility of this cell system in the evaluation of in vitro enzyme induction (Figure 1).
Estimates of in vivo metabolic drug clearance can be determined from in vitro metabolism kinetic data. Metabolic stability studies are typically performed to estimate a drug candidate’s metabolic half-life and intrinsic clearance rates, which are major determinants of in vivo drug efficacy. Compounds with short half-lives may require multiple doses to maintain effective plasma levels, whereas compounds with slower elimination kinetics require fewer doses. Unlike other cell lines (e.g., HepG2 and Fa2N-4) HepaRG™ cells have expression levels of key metabolic enzymes and nuclear receptors consistent with levels observed in PHH, and therefore, are more suitable to assess the metabolic stability of candidate compounds (Figure 2).
The liver plays a central role in metabolizing and eliminating xenobiotics and as a result is susceptible to injury from drug toxicity. Liver toxicity has led to withdrawal or severe use limitations of marketed drugs and is a major problem in drug development. HepaRG™ cells are a metabolically competent system and tolerant of long culture periods (i.e. ≥22 days). In addition, they are well suited for in vitro determinations of acute and chronic toxicity resulting from intrinsic and/or metabolism-based mechanisms (Figures 3 and 4).
Transporters often work together with drug-metabolizing enzymes in drug absorption and elimination, resulting in altered drug efficacy and adverse drug effects. HepaRG™ cells have superior expression levels of key uptake and efflux transporters compared to other cell lines, and expression levels closely resembling those of human hepatocytes (Figures 5 and 6).
- Aninat C et al. (2008) Crit Care Med 36:848–854.
- Lübberstedt M et al. (2011) J Pharmacol Toxicol Methods 63:59–68.
- Aninat C et al. (2006) Drug Metab Dispos 34:75–83.
- Guillouzo A et al. (2007) Chem Biol Interact 168:66–73.
- Le Vee M et al. (2006) Eur J Pharm Sci 28:109–117.
HepaRG™ is a trademark of BioPredic International.
Limited Use License
HepaRG™ cells are patented and their use is strictly limited; consider the cells as a single-use, disposable product that must be destroyed upon conclusion of a study or experiment. Propagating, reproducing, cloning, subcloning or any other use of the cells following the conclusion of a study is prohibited. Use of the cells to produce or manufacture commercial products for general sale or for use in the manufacture of products intended for general sale is prohibited. Transfer of the cells to anyone not employed within the same organization, whether for financial benefit or not, is also prohibited.