What is the role of ADME in drug discovery?

ADME | Tebu Bio

ADME is an abbreviation in pharmacokinetics (a branch of pharmacology that studies how substances act and remain in organisms) for “Absorption, Distribution, Metabolism, and Excretion”.

It refers to the stages a pharmaceutical compound goes through within an organism. These four stages influence how drugs are broken down, assimilated and remain in the body, which will thus influence their performance and pharmacological activity.

Sometimes, liberation and/or toxicity are also studied, which is why you can find varying acronyms such as LADME, ADMET, or LADMET.

Understand drug development

Pharmacokinetics (or PK) is a branch of Pharmacology that studies the interactions between drugs and organisms. Any substances that have medicinal properties are considered as “pharmaceuticals”.

More broadly, Pharmacology comprises two main areas: PK and Pharmacodynamics (PD). PD is more concerned with the direct biochemical and physiologic effects of drugs.

Already you can see a clear link to why these fields are crucial to the development of new drugs, in early research, target validation and discovery programs. But let us dig in a little deeper.

The IUPAC (International Union of Pure and Applied Chemistry, that represents chemists in a number of countries) has an official definition of PK:

– First, it is the process of the uptake of drugs by the body, the biotransformation they undergo, the distribution of the drugs and their metabolites in the tissues, and the elimination of the drugs and their metabolites from the body over a period of time.

– Second, it is the study of more such related processes.

ADME is among the basics of new drug research, since nine out of ten new drugs fail in clinical testing. It is carried out during pre-clinical testing, just like high-throughput screening (HTS). HTS’ goal is to “screen” the molecules that will have a desired effect, but while HTS mainly allows to recognise active compounds, ADME allows for a better understanding of these molecules’ full effect.

The main reasons for this low success rate lies with the very concept of pre-clinical testing: laboratory rat and mice are too genetically homogeneous and success on these species does not mean success in humans by a long shot – indeed, mice and rats have very different metabolic pathways and reactions from humans.

Therefore, before we even begin clinical trials, it is highly important to understand human metabolism by having precise and correct answers to these questions: how will the drug affect the human body, how will it be assimilated, how long will it remain in the body, etc. This is why pharmacology is key in the development process.

What are each part of ADME concerned with?

The A stands for Absorption/Administration

For a compound to reach whichever part of the body it is supposed to impact, most of the time, it will be absorbed in the bloodstream. This is usually done via the digestive tract; think about pills for instance: the active substance is contained within an envelope that will dissolve in the digestive acids and thus release the drug within, that will be absorbed within the bloodstream in the intestines.

PK will be studying how, for instance, compound solubility, gastric emptying time, intestinal transit time, chemical instability in the stomach, and inability to permeate the intestinal wall will affect how much of the drug is absorbed and how.

Absorption is thus a key part of what is called bioavailability; i.e., how much of the drug (in percentage) actually reaches the cardiovascular system. It follows that drugs that have been injected directly into the bloodstream (intravenously) have a bioavailability of 100%, by definition. In this regard, the way a substance is administered is also an important point to consider, as injections can be both intravenous or intramuscular, and other methods exist such as skin penetration, inhalation, oral ingestion, etc.

Each way to administer a substance will change the “path” it takes within the body, and thus its potential effects.

The D stands for Distribution

Once a drug has been absorbed into the system, it needs to reach the targeted area – whether organ(s), muscle(s), etc. It does so through the bloodstream or through other means of administration.

The more “phases” or “distribution processes” the substance goes through, the less concentrated it usually becomes (if a drug is inhaled for instance, it will go from the respiratory system and its organs to the circulatory system, each “barrier” most likely lowering its potency or bioavailability).

Basically, distribution refers to the transfer of a drug from “point A” (administration site) to “point B” (target). Regional blood flow rates, molecular size or polarity can affect how drugs are distributed within an organism. The blood-brain barrier can also become a complex challenge to solve regarding distribution.

The M stands for Metabolism

Much like food, drugs begin breaking down as soon as they enter the body (think back to the digestive system and how food starts breaking down under the effect of saliva right after ingestion). And so, as metabolism occurs, the initial compound is broken down into smaller molecules that will be carried to the liver for “filtration” by cells called hepatocytes.

The initial compound is converted to new compounds called metabolites (by definition, the end product of metabolism, the small molecules that are left). Depending on the chemical composition, metabolism usually reduces a drug’s effects on the body, but it can happen that metabolites may be more active than the original drug (this is what happens in the case of “prodrugs”, which are metabolised by the body into an active drug).

And the E stands for Excretion

Both compounds and metabolites are eventually taken out from the body by a process called “excretion”. Excretion is extremely important to the body’s normal functioning: as a matter of fact, an accumulation of foreign substances can adversely impact both the normal metabolism and the subject’s health. It is thus the body’s way of “eliminating” these substances.

Depending on the molecules in question, they are either taken out through the kidneys (and then evacuated out of the body with urine), the liver (they are then processed through the gut then evacuated with feces) or through the lungs (the clearest and simplest example being, the carbon dioxide (CO2) you excrete every time you breathe out).

Why is ADME a key part of drug discovery?

PK thus studies the variation in drug concentration with time as a result of each of these processes within ADME.

It aims to answer questions pertaining to dosage, administration, rate and extent of absorption, distribution rate and elimination rate. Simply put, it examines what the body does to the drug (while PD is more concerned with the drug’s effect on the body).

Understanding these interactions is key in understanding drug candidates’ final effects. For instance, drug binding is a key point to be considered: since many drugs will strongly bind with proteins in the blood or food in the gut it is crucial to know what the plasma protein binding degree will be – the degree to which medications attach to proteins within the blood – so as to maintain the right amount of free drug (active drug that is not bound to protein) in the system.

The two most important concepts in PK are “drug clearance”, the rate at which a drug is eliminated from the system; and bioavailability. In order of importance, the two next ones are DDIs (drug-drug interactions) and metabolism-related drug reactions.

So for any program of drug discovery, ADME is key before even getting to clinical trials because it will answer necessary preliminary questions pertaining to drug interactions with the body.

Improper PK studies are responsible for a huge part of drug research failures.


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