Many new developed pharmaceuticals turn out to be toxic, even after getting release into the market due to their unexpected side effects. These adverse drug reactions cause significant health issues to patient’s health and as well as cause financial loss to pharmaceutical industry due to post-licensing drug withdrawal from market.
Adverse drug reactions are of various types depending on the affected organ system in the body. Out of all, drug-induced liver toxicity and acute liver failure are major reasons for the withdrawal of an approved drug from the market.
Importance of liver in drug metabolism
When the pharmaceutical drug is absorbed in the body; there are many sites in the body that are involved in drug metabolism including the gut wall, lungs, kidney and plasma. However, liver is majorly involved in metabolizing foreign compounds and thus the major target for toxicity caused by drugs. The metabolism of a compound in the liver determines how pharmaceuticals will be cleared from body. In addition, drugs can act as promoter or inhibitor of liver’s drug metabolism enzymes that can also further affect the metabolism of drugs. Therefore, for development of new drug or extension of therapeutic utility of drug, it is critical to study drug-liver interaction and their potential hepatoxicity.
Application of primary liver cells or hepatocytes
The pre clinical experiments provide limited data due to differences in liver metabolic pathway in different species. To overcome limitations associated with animal studies, researchers and pharmaceutical industry employs alternative liver models in research such as microsomes, transfected cell lines and primary human hepatocytes. Cultured hepatocytes are gaining popularity in the pharmaceutical industry for the assessment of hepatotoxic potential of new molecules. Hepatocytes provide a physiologically-relevant cell type that exhibits all the characteristic enzymes, co-factors, transporters and provide environment for drug metabolism that closely mimics that of in vivo. As primary hepatocytes in culture retain hepatic key functions so constitute a valuable tool to identify chemically induced cellular damage.
The use of primary hepatocytes in research has notably made significant contribution in the understanding of mechanisms responsible for hepatotoxicity (disruption of cellular energy status, metabolic activation, oxidative stress, covalent binding, etc.). With the use of primary hepatocytes, new pharmaceuticals can be rejected at a much earlier phase if it turns out to be toxic that would directly lead to a reduction in the number of animal experiments and further clinical trials. Primary cells will also be advantageous in the field of personalized medicine also. The primary cells derived from the patient itself will be used to determine the safety and effectiveness of medication in particular patient.
In conclusion, freshly isolated primary human hepatocytes are optimal choice to study drug metabolism and toxicity studies because they maintain most of the in vivo activities of liver.
Application of hepatocyte- like cells to enhance hepatic safety risk assessment in drug discovery. Williams DP. 2018 Philosophical Transactions B.
The use of hepatocytes to investigate drug toxicity. GOmez-Lechon MJ et al 2010 Methods Mol Biol.