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Cultured hepatocytes as investigational models for hepatic toxicity: practical applications in drug discovery and
R G Ulrich1, J A Bacon, C T Cramer
1Investigative Toxicology Unit, Upjohn Laboratories, Kalamazoo, MI 49007, USA.
Abstract:
Drugs can fail at any phase during discovery, preclinical or clinical development due to unacceptable levels of toxicity, and liver is commonly the principle target organ. Investigational toxicology methods, using appropriate models and hypotheses, can often resolve problems, identify toxic chemical substituents and salvage therapeutic discovery programs. While in vivo models are used to investigate hepatic drug effects in the context of toxicokinetics and systemic influences, cell culture models provide in vitro systems for investigating specific mechanisms in a precisely controlled environment. Using primary hepatocytes isolated from laboratory animals, we have explored several drug-induced hepatic disorders that surfaced during different phases of drug discovery and development. Additionally, the use of human hepatocytes has allowed us to address concerns for human exposure, examine human relevance of animal data, and provide perspective on problems encountered in clinical trials.
Insights
Investigational toxicology methods using hepatocyte models can identify drug-induced liver injury and salvage therapeutic programs. These models help resolve toxicity issues during drug discovery and development.
Area of Science:
- Hepatotoxicity and Drug Development
- Toxicology and Pharmacology
Background:
- Drug development frequently encounters failures due to unacceptable toxicity, with the liver being a primary target organ.
- Investigational toxicology methods are crucial for identifying toxic compounds and salvaging drug discovery programs.
Purpose of the Study:
- To explore drug-induced hepatic disorders using primary hepatocytes during various stages of drug discovery and development.
- To assess the human relevance of animal data and address concerns regarding human exposure to drug candidates.
Main Methods:
- Utilized primary hepatocytes isolated from laboratory animals for in vitro investigations of drug-induced liver injury.
- Employed in vivo models to study hepatic drug effects within the context of toxicokinetics and systemic influences.
- Incorporated human hepatocytes to evaluate human relevance and clinical trial-related issues.
Main Results:
- Successfully explored various drug-induced hepatic disorders using both animal and human hepatocyte models.
- Demonstrated the utility of cell culture systems for mechanistic investigations in a controlled environment.
- Provided insights into human exposure concerns and the clinical relevance of preclinical findings.
Conclusions:
- Primary hepatocytes, both from animals and humans, are valuable tools for investigating drug-induced liver toxicity.
- In vitro and in vivo toxicology models can effectively identify toxic liabilities and support therapeutic discovery.
- Hepatocyte models aid in bridging the gap between preclinical data and clinical outcomes in drug development.