ADME assays are used in drug discovery and development to determine the metabolic and safety profiles of candidates on a high throughput scale. Pharmaceutical companies rely on their research labs to conduct further studies on:
• Permeability and protein binding
• Metabolic stability, CYP inhibition, and metabolite profiling
• Drug-drug interaction and enzyme induction
• In vivo animal PK
Permeability and protein binding:
A drug is more permeable if it is water soluble. It can permeate membranes, chemicals or biological degradation. When a drug does not have the ability to get absorbed, it has to be optimized using a variety of research methods. Modern science uses Caco-2 and MDR1-MDCK cell lines to measure the drug permeation in the intestines. To be effective, the drug has to cross the intestinal epithelium. After the compound permeates, it enters the blood stream. When it enters the plasma, it binds itself to various blood constituents. Each compound has its own properties and a lab studies to find the exact property of each compound.
Metabolic stability, CYP inhibition and metabolite profiling:
The body has the ability to rid itself of compounds from blood circulation. It is called drug metabolic clearance. When the entire body rids itself of the drug, it is called systemic clearance. Hepatic clearance takes place in the liver. First, metabolic stability in vitro is established and then this measurement is used to predict in vivo clearance. Modern labs perform metabolic stability in different species of fresh and cryopreserved hepatocytes, liver microsomes, liver S9 fraction, liver cytosol and extrahepatic tissues, such as intestine, brain, kidney, lung, skin, and so forth. This helps discover a better pathway for metallization and also addresses issues related to the same.
Drug-drug interaction and enzyme induction:
Administration of drugs sometimes results in an increase in enzymes in Phase I and Phase II metabolism. Some drugs have narrow therapeutic windows and thus the need for enzyme induction leads to administration of xenobiotics that can be toxic. The drug metabolite department discovers induction levels from gene, protein, and Phase I and II enzymes.
In vivo animal PK: Rodents and non-rodent species are used to screen and study complex issues to help design a pathway and protocols for new drug discovery. The use of software allows PK data analysis and analytical report creation for clients.
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