ADME Pharmacokinetics Studies

Absorption, Distribution, Metabolism and Excretion

• Absorption ‐ Route of Drug Delivery

– Where absorbed?

• Distribution ‐ Where does the drug go, where does it need to go and what are the implications?
• Metabolism Metabolism ‐ This will occur and could impact several several variables variables.

– Could be used to your advantage ‐ Prodrugs.

• Excretion – How is the drug eliminated?
• Pharmacokinetics is concerned with the variation in drug concentration with time as a result of absorption, metabolism, distribution and excretion

– Drug dose, route of administration, administration, rate and extent of absorption, absorption, distribution distribution rate (particularly to site of action) and rate of elimination.

– Pharmacokinetics may be simply defined as what the body does to the drug.

– Pharmacodynamics defined as what the drug does to the body.

in vivo ADME Services
We conduct a range of studies in rats and mice (other species are possible), including:

• Pharmacokinetics including dosing via i.v., oral, subcutaneous, intraperitoneal or intramuscular routes
• Calculation of basic PK parameters
• Bioavailability following dosing by any of these routes
• Metabolism studies, including metabolite identification (mass spectral and/or after enzymatic incubations)
• Recovery of parent drug and/or metabolites in urine, faeces or bile
• Tissue distribution studies, including dosing with nonradiolabelled or radiolabelled (supplied by the Sponsor)versions of the investigational drug

in vitro ADME Services
We conduct in vitro screening including:

• Metabolic stability screening or profiling due to Phase I (CYP450) or Phase II (glucuronidation / sulfonation) processes
• Studies conducted using cryopreserved hepatocytes (pooled human or male or female animal), microsomes or S9 as appropriate
• Identification of CYP450 isoforms responsible for metabolism using recombinant human CYPs
• Isolated perfused rat liver – TetraQ-ADME has many years experience with this model
• Caco-2 cell in vitro absorption studies

Drugs are specifically designed using ADME principles; however, chemicals for commercial use are not designed with any guidelines targeting ADME.

Absorption

There are four main routes of exposure:

– 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.
– Dermal through skin or eye contact.
– 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.
– 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 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:

– Passive diffusion. Diffusion occurs through the lipid membrane from a high to low concentration (aka concentration gradient).
– Filtration. Diffusion occurs through aqueous pores, still from high to low concentration as a driving mechanism.
– Special transport. Transport is aided by a carrier molecule. Can move against the concentration gradient (low to high).
– 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.

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