What is Preclinical ADME Studies?

ADME studies – ADME is an abbreviation in pharmacokinetics and pharmacology, stands for absorption, distribution, metabolism and elimination of chemicals and drugs to define the impact in a human body. Toxicology testing is a significant event before an introduction of new drugs into the market. However, drug development is a very crucial stage of the pharmaceutical and biotechnology manufacturer as it is attributed to high costs at the various stages of drug development. Thus, one of the key factors linked to the last stage drug failure is due to inability of new drug candidates to meet human and animal safety profile.

In order to overcome this barrier of drug failure, ADME toxicology testing has a major advantage to enter in early drug development phase of preclinical trials. ADME toxicology testing influence the drug levels and kinetics of drug exposure to the body tissue and hence facilitated the performance in pharmaceutical manufacturing by minimizing drug discovery time, complications in testing and reduction in overall cost in drug development. Thereby, preclinical ADME toxicology testing is a substantial application in drug discovery venture capital (VC) industries to make financial decisions in corresponds to significance and scope in the drug discovery firms, which is expected to gain more traction of the ADME (absorption, distribution, metabolism and elimination) toxicology testing market over the forecast period.

Absorption

There are four main routes of exposure:
I) Inhalation through the respiratory system: a chemical in the form of a gas, vapor or particulate that is inhaled and can be excreted or deposited in the respiratory system.
II) Dermal through skin or eye contact.
III) Ingestion through the gastrointestinal system: Absorption through the digestive tract. Ingestion can occur through eating or smoking with contaminated hands or in contaminated work areas.
IV) Injection: Introducing the material directly into the bloodstream. Injection may occur through mechanical injury from “sharps.”

To be absorbed, a substance must cross one of the layers of cells that keeps “us” “in” and the rest of the world “out”: skin (including mucus membranes), lung, and the gastrointestinal (GI) tract. Most substances are absorbed by passive diffusion through membranes. A small number of biologically important atoms and molecules are actively taken up by cells. Examples include sodium, potassium, and calcium ions, amino acids, small sugars (mono- and di- saccarides). If your substance is very similar to one of these, there is an increased chance of cellular uptake. Solubility into membranes is the primary factor affecting absorption.

Distribution

The compound next needs to be able to move from the site of absorption to other areas of the living system if it is to be distributed. Not all compounds could move easily. Most often movement is via the bloodstream but other compounds may move cell-to-cell as well. In general, there are four main ways by which small molecules cross biological lipid membranes: (Links to an external site.)

I) Passive diffusion. Diffusion occurs through the lipid membrane from a high to low concentration (aka concentration gradient).
II) Filtration. Diffusion occurs through aqueous pores, still from high to low concentration as a driving mechanism.
III) Special transport. Transport is aided by a carrier molecule. Can move against the concentration gradient (low to high).
IV) Endocytosis. Transport takes the form of pinocytosis for liquids and phagocytosis for solids.
Many times the mechanism of transport for a certain chemical is unknown, and so we must judge its potential toxicity using other variables (such as molecular weight, ionization (pKa), and octanol/water partition coefficient (logP)).

Metabolism

Compounds begin to break down in the body by a family of enzymes in the liver called the Cytochrome P450 system. These enzymes can convert chemicals to reactive oxygen species (ROS), reactive intermediates, free radicals, and others. For example, redox reactions and potential, with a transfer of electrons, influence the toxicity of a chemical at the intracellular level. Scientific advances in toxicology and chemistry are starting to allow scientists to better understand these kinds of interactions, and they are able to map out more specific pathways, called Adverse Outcome pathways (AOPs). It is through understanding these pathways that a new generation of chemicals will be safely designed by chemists and others.

Excretion

Most excretion occurs through the kidneys as urine or as feces. Excretion is dependent on the process of kidney filtration at the glomerulous, and is largely based on molecular size and charge. Some molecules can be excreted through the skin as sweat and still some may be excreted through the lungs via gas exchange. If excretion is not a complete process, the molecule or metabolic by-product can bioaccumulate and impact living systems adversely. If a compound is lipid-soluble, it will bioaccumulate more quickly in adipose tissue. Bioaccumulation of lipid-soluble compounds such as DDT has been shown to be correlated with adverse health effects such as diabetes, heart disease, obesity, etc.

Medicilon’s pharmacokinetics department offers the clients a broad spectrum of high quality of services in the areas of in vitro ADME, in vivo pharmacokinetics and bioanalysis services, ranging from small molecules to large molecules, such as protein and antibody. The animal species involved in our services are non-human primate, canine, mice, rat, rabbit and etc. Meanwhile, non-human primate experimental platform and isotope platform for protein/antibody are certified by the Shanghai government.

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