Rat HepatoPac™

Introducing Rat HepatoPac - a next generation in vitro rat micro-liver technology. Rat HepatoPac co-cultures contain primary rat hepatocytes organized into colonies of prescribed, optimized dimensions and surrounded by supportive, non-parenchymal cells which maintain in vitro functionality for over 4 weeks. This extended longevity allows for long term, low-dose toxicity testing as well as assessment of intrinsic clearance and metabolite profiles of low turnover compounds. All Hepregen DMPK and Toxicology Services can be performed using Rat HepatoPac.

Rat HepatoPac Co-cultures:

  • Retain viability for over 4 weeks in vitro
  • Enable evaluation of low clearance compounds
  • Allow chronic toxicity studies
  • Combine with Human HepatoPac to identify species-specific toxicity
      

Rat HepatoPac™ Characterization

Rat HepatoPac provides highly functional enzyme activity of Phase I & Phase II enzymes as well as consistent morphology and functional readouts such as albumin secretion for over 4 weeks. Data is presented summarizing the morphology, functional readouts and the activity profiles of various rat CYPs in Rat HepatoPac co-cultures for over 32 days. Rat HepatoPac remains viable and highly functional for 4 weeks rather than several days observed using conventional hepatocyte cultures.

 

Morphology

 

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Rat HepatoPac co-cultures were created and maintained in vitro for over 4 weeks. No substantial changes to the morphology of micropatterned co-cultures were observed throughout the culture period. Transport of a fluorescent dye via MRP-2 demonstrates the robust network of bile canaliculi between hepatocytes.

 

Phase I CYP Activity

 

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Activity of Phase I CYPs assessed using mass spectrometry to detect metabolites: midazolam hydroxylation by CYP3A, dextromethorphan demethylation by CYP2D, diclofenac hydroxylation by CYP2C, buproprion hydroxylation by CYP2B, and lauric acid hydroxylation by CYP4A.

 

Phase II Enzyme Activity

 

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Activity of Phase II enzymes assessed using mass spectrometry to detect Phase II metabolites: 7-OH-coumarin glucuronide and 7-OH-coumarin sulfate.

 

Activity Profile Substrate Usage

 

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References for rat specific probe substrates:
1.   Madan et al. (1998) Effect of cryopreservation on cytochrome P-450 enzyme induction in cultured rat hepatocytes.  DMD; Vol. 27, No. 3 (327-335).
2.  Kobayashi et al. (2002) Substrate specificity for rat cytochrome P450 (CYP) isoforms:  screening with cDNA-expressed systems of the rat Biochemical Pharmacology; (889-896).
3.  Burke et al. (1994) Cytochrome P450 specificities of alkoxyresorufin o-dealkylation in human and rat liver.  Biochemical Pharmacology; Vol. 48, No. 5 (923-936).

Improved Toxicity Testing using Rat HepatoPac

 

Use of in vitro rat liver cell cultures are important tools in detecting drugs associated with hepatic adverse drug reactions in preclinical development. Animal-based in vitro assays are necessary as they allow correlation of in vitro metabolic stability and metabolic profiles with in vivo metabolism studies. Unlike Rat HepatoPac which is viable for weeks in culture, alternative model systems such as rat primary hepatocyte monocultures, hepatocyte suspensions and sandwich cultures lose functionality (i.e. drug metabolizing enzyme activity) within a few days. Thus, Rat HepatoPac enables unique opportunities for improved toxicology testing including chronic and low-dose studies. Additionally, Rat HepatoPac co-cultures are micropatterned on industry-standard multiwell plates for streamlined, higher throughput in vitro assays.

Featured Resources

Rat HepatoPac™ Specification Sheet
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Poster: Assessment of Rat and Human HepatoPac™ to Detect Compounds that Cause Drug Induced Liver Injury in Humans
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The rate of albumin secretion and urea synthesis were consistent throughout the 32 day culture period demonstrating the extended functionality of in vitro Rat HepatoPac.

Related Information

Toxicology Services
HepatoPac™ Technology HepatoPac™ Literature


Featured Downloads

Rat HepatoPac™
Specification Sheet

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HepatoPac™ for the Prediction of DILI

Poster - Assessment of HepatoPac to Detect Compounds that Cause Drug Induced Liver Injury in Humans

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