Solutions for Liver Metabolism Research

Caltag Medsystems offers many solutions for researchers working in the toxicology field.

With research areas including in-vitro absorption, distribution, metabolism and excretion (ADME) applications; innovative modes of culture; hepatotoxicity screening and mechanistic testing applications; infectious disease; and drug metabolism studies, the company provides the HepaRG cell line and options for quantifying Cytochrome P450 (CYP) in drug-drug interactions as tools to further research in these areas.

Through its suppliers, Caltag Medsystems offers hepatocyte cell line HepaRG™.

HepaRG™ cells have unique properties. They maintain hepatocyte functions while supporting the complete replicative cycle of the Hepatitis B Virus (HBV). This means they can be used in toxicology studies as an alternative to fresh hepatocytes. The HepaRG™ cell line can be used in a wide range of applications.

HepaRG™ has many key advantages over fresh hepatocytes and other hepatic cell lines, including:

• The capacity to produce early hepatic progenitor cells and completely mature human hepatocytes
• A morphology and metabolic capacity similar to human primary hepatocytes
• The first human hepatoma cell line to express main CYPs, functional nuclear receptors and major sinusoidal and canalicular hepatic drug transporters
• Overcomes limited availability of liver tissue and excellent batch-batch reproducibility and sub-cultures
• CYP activities and expression of canalicular drug transporters can be increased by classical inducers
• A robust cell-based system to evaluate the metabolism of test compounds
• A suitable model for high throughput screening of chemicals
• A unique and exclusive model for in vitro pharmacological and toxicological studies
• Usable and stable for at least 4 weeks once differentiation is achieved, ideal for long-term studies
• Can support the complete replicative cycle of HBV

For those customers working on drug metabolism, Caltag Medsystems can provide Silensomes™. Drug-drug interaction can significantly impact drug safety and efficacy. Prediction of this risk of drug-drug interactions is a requisite in the development of a new drug candidate.

In-vitro identification and measurement of the contribution of the major cytochrome P450 enzymes involved in the human metabolism of a new drug candidate, also called CYP phenotyping, helps predict the impact of co-administered drugs (perpetrators) on the pharmacokinetics of the new chemical entity (victims).

Until now, a battery of in-vitro tests recommended by the regulatory agencies such as the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) are required for this CYP phenotyping assay. These tests (correlation analysis, antibody or chemical inhibition and metabolism by recombinant human enzymes) have a number of disadvantages:

• No direct quantitative measurement of the contribution of each CYP in the metabolism of a drug (correlation analysis)
• Model is not fully representative of the liver enzyme profile (e.g. human recombinant CYP450)
• Lack of specificity (e.g. anti-CYP antibodies and chemical inhibitors)

To overcome the disadvantages of the current methodologies, our supplier has developed in a patented new in-vitro drug development model. Silensomes™ are a single unique and representative model, capable of directly quantifying and predicting the contribution of CYP enzymes in drug metabolism. Silensomes™ are human pooled liver microsomes (HLMs) in which one specific CYP has been chemically knocked out (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4).

Each Silensomes™ is available ready-to-use with each showing high specificity and efficiency of their targeted CYP inhibition (>80%) and only minor impact (<20%).

The key advantages of Silensomes™ include:

• Irreversibly inhibited CYPs
• For initial rate conditions
• For saturating conditions
• One single model for CYP phenotyping assays, instead of a battery of in-vitro tests
• Quantitative: the true contribution of the CYP450 in the metabolism of the compound can be measured
• A powerful model with excellent specificity, potency, stability and predictability to ensure reliable extrapolation of the drug-drug interaction risk
• More representative of in-vivo, using human liver microsomes rather than recombinant enzymes isolated from non-mammalian cells

Contact Caltag Medsystems to learn more about these exciting products.