Liver
cells
To assess the
toxicologic and pharmacologic properties of drugs and other xenobiotics,
in-depth knowledge of their bio-transformation is of decisive importance.
The liver is
the most important organ for biotransformation in the body and exhibits the
highest levels and the most complete spectrum of drug metabolising enzymes.
Substances taken orally are absorbed in the intestine and reach the liver via
the portal blood.
Isolated
liver cells show enzyme activities that reflect the in-vivo state, and
therefore, are a valuable system to study liver drug metabolism. They offer an
easy, convenient and relevant in-vitro model for basic research, toxicologic
studies, drug development as well as pre-clinical drug testing.
In future, advances in stem cell technology are expected to enable scientists to control stem cell differentiation into liver cells, thus providing an unlimited supply of such cells for research purposes.
Human cell applications and products are ethnically defined and restricted. Thailand, with its population of 62 million and its rapid economic growth, is a significant emerging market for biologic and pharmaceutical products.
The research applications of human liver cells in drug discovery and development are
as follows:
1. Drug Metabolism
Human liver cells, and processed material such as microsomes and hepatocytes, are essential for gathering information about the metabolism of potential new drugs before they are tested in living subjects. Such information speeds up the process of discovery and development of better and safer drugs to treat every imaginable disease, from the common cold to cancer and AIDS. With this knowledge, scientists are able to focus their efforts on those drug candidates that are most likely to be safe and effective. Doing these studies with human tissue also reduces the number of laboratory animals that are sacrificed for research. In addition, the enzymes that metabolize some drugs are not present in some people. Pharmaceutical companies try to avoid developing drugs that are metabolized by those enzymes due to the wide variation in effectiveness of those drugs in different people.
2. Drug-drug interactions
Many people, particularly the elderly, are required to take a wide variety of medications on a routine basis and must be very careful to avoid certain combinations of drugs which can interact to cause unwanted side effects and/or toxicity. A drug that enhances or inhibits the metabolism of another drug could reduce its effectiveness or cause toxic side effects, respectively. Researchers use human liver tissue to investigate potential interactions between different drugs; in particular, potential interactions between new drug candidates and other drugs that are likely to be administered with them are probed. The results help determine whether specific clinical trials are needed to address drug interactions and enable doctors to avoid potentially dangerous combinations of drugs.
3. Drug toxicity
The liver is the major site of conversion of drugs and other chemicals into products (metabolites) that are excreted. However, in some cases the metabolites may be toxic to the body. The use of fresh liver cells enables pharmaceutical researchers to investigate the possibility of toxicity due to a drug or one of its metabolites at an early stage in the drug development process. With this knowledge, they can focus their efforts on drugs that are likely to be safe when they are eventually tested in people. This not only speeds up the process of drug development, but also reduces the number of laboratory animals that are used.
4. Species selection for toxicity studies
One of the many government requirements that must be satisfied prior to testing a potential new drug in humans is that the drug candidate must be tested in laboratory animals. Critics point out that animal studies do not necessarily predict what will happen in people, because of basic physiological differences between different species. Some of these concerns can be eliminated through the use of human liver cells, by comparing the metabolism of a drug candidate in human liver vs. liver cells from various animal species. The results enable researchers to select the most appropriate animal species for pre-clinical testing of new drugs.
5. Reducing the use of laboratory animals
Prior to the availability of human liver cells for studies of drug metabolism, drug toxicity and drug-drug interactions, it was necessary to use cells obtained from laboratory animals such as rats, mice and dogs. Although animal liver differs in many important ways from human liver, some studies were needed and there was no alternative. Now that human liver cells is available for research, researchers can study a more relevant experimental model while simultaneously using fewer animals.
6. Advantages of human liver cells vs. animal liver cells
A large number of studies of drug metabolism, drug toxicity and drug-drug interactions have demonstrated that many drugs are handled differently by animals than humans and/or have different effects on animals than humans. In some cases, there are more similarities than differences, but in others the differences are dramatic. It is nearly impossible to predict beforehand whether a potential new drug will be metabolized in the same way and to the same degree by a laboratory animal and by humans. The availability of human liver cells, therefore, is crucial to the process of discovering and developing safe and effective new drugs.
Further reading:
Gebhardt R., Hengstler J.G. et al. New Hepatocyte In Vitro Systems for Drug Metabolism: Metabolic Capacity and Recommendations for
Application in Basic Research and Drug Development, Standard Operation Procedures. Drug Metabolism Reviews, Vol. 35, Nos. 2 & 3, pp. 145–213, 2003
Brandon E.F., Raap C.D. et al. An update on in vitro test methods in human hepatic drug biotransformation research: pros and cons. Toxicology and Applied Pharmacology 189, 233–246, 2003
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