Product Applications

Product Applications

CellzDirect's experienced technical support and scientific teams would be happy to discuss all of the applications for which our products may be used. Below is a quick reference guide that might help to determine the most appropriate product for your application. We would be happy to help match your specific need to a product type or product lot that we have available.

Drug Metabolism Product Applications

Application	Microsomes	S9 Fractions	Fresh Hepatocytes	Cryopreserved Hepatocytes
Inhibition
Reaction Phenotyping
Metabolic Stability
Intrinsic Clearance
Metabolic Profiling /Met ID
Induction

Product Background

The primary goal of pharmaceutical companies is to discover and develop safe and effective drugs. The drug discovery process is costly and time-consuming, making drug discovery and development a financially risky business. It has been estimated that it requires hundreds of millions of dollars and at least 10 years for a single new chemical entity (NCE) to reach the marketplace as a new drug. In order for a NCE to make it to market as a safe and effective drug, it must pass through a series of hurdles. The first hurdle to overcome is passing from drug discovery to the preclinical phase. The preclinical phase evaluates initial parameters such as: drug metabolism, pharmacokinetics, and toxicity in animals. After successfully passing through the preclinical stage the NCE is then submitted as an investigational new drug (IND) application to the Food and Drug Administration (FDA). If approved, then the IND may enter the full development process: Phase I (safety and tolerability in healthy volunteers); Phase II (efficacy in a small number of patients); and Phase III (efficacy in a large population of patients). If the drug passes all three clinical (human) phases, it is submitted to the FDA as a new drug application (NDA). Upon FDA approval, the drug then enters the market place. It is also worth noting that approximately 1 in 4 marketed drugs generate sufficient revenue to recover the costs associated with its discovery and development.

A significant factor that increases costs in the drug development process is the high failure rates of NCEs resulting in many false starts or unnecessary development costs. It has been estimated that 1 in 5000 compounds make it from drug discovery to the preclinical stage. In addition, only 1 in 25 compounds that make it from the preclinical stage to the IND stage will make it to market as a new drug.

The ever-increasing number of NCEs synthesized by pharmaceutical companies has prompted the development of research methods for rapid screening. Present research efforts are directed at developing a series of in vitro assays that could serve as reliable indicators to minimize the attrition rates of new chemical entities. By utilizing in vitro models, pharmaceutical companies are now focused on reducing these preclinical and clinical failure rates by attempting to accurately evaluate efficacy and safety much earlier in the drug discovery process. Ideal in vitro models to predict drug metabolism are derived from human liver tissues such as intact liver cells (hepatocytes) and subcellular fractions of the hepatic smooth endoplasmic reticulum (microsomes).

Microsomes and hepatocytes are effective in vitro models that are used as biological tools for obtaining information about the metabolism of NCEs as they move through the drug development process. The majority of drug metabolism occurs in the liver by cytochrome P450 enzymes (CYP). These enzymes are primarily located in subcellular organelles (the smooth endoplasmic reticulum). Presently, five major CYPs have been identified to be involved in the vast majority of all marketed drugs: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Significant factors in eliminating NCEs as potential drugs are CYP dependent drug-drug interactions and rapid CYP dependent metabolism of a drug (metabolic stability). CYP-related drug-drug interactions occur either when one drug inhibits or increases the metabolism of another co-administered drug. For example, the FDA recall of the first non-sedating antihistamine (Seldane) was based on it's potential to reach lethal blood levels when co-administered with an antibiotic such as erythromycin (1997). In this case, both drugs are primarily metabolized by CYP3A4, and subsequently when co-administered, their elimination phases are hindered. The clinical result was an increase in the blood levels of Seldane to toxic levels resulting in lethal arrythmias. Microsomes and hepatocytes are effective in vitro models that can be used to predict drug-drug interactions as well as metabolic stability. Pharmaceutical companies routinely use microsomes and hepatocytes in the drug discovery process in attempts to reduce the attrition rates of NCEs and the sky rocketing costs of the drug development process.

Prior to the availability of human tissues for medical research, scientists had to rely on data obtained from animals and animal tissues. Unfortunately, animal studies do not adequately predict what will happen in humans because of the basic physiological differences between each species. With the advent of obtaining consent of human tissues to be used in medical research, scientists can better predict how a new drug will fare in humans. It cannot be overstated that the availability of human tissue is crucial to developing more safe and effective drugs.

CellzDirect provides fresh human hepatocytes on a frequent basis as suspensions and in multi-well plates. For notification of fresh hepatocyte availability, please register for our RapidAlert service. Cryopreserved human suspensions are also available from a wide range of donors. Fresh animal hepatocytes are provided on a scheduled monthly basis as suspensions or in multi-well plates. All species and strains of animal toxicology models are available as cryopreserved suspensions. Custom isolations are provided upon request. Human and animal subcellular fractions, including liver microsomes, S9, and cytosol, are also available. CellzDirect also offers a comprehensive selection of ATP-binding cassette (ABC) transporters, through our partnership with GenoMembrane.

Our experienced scientific staff conducts ongoing research with hepatocyte culture systems to remove technological barriers to in vitro testing, improve cell quality and extend their utility. With CellzDirect’s support and cell products, scientists are better able to conduct research that accelerates the discovery of safe and effective drugs.