Developing new medicines is a complex process. A key challenge involves understanding how the body interacts with a drug, a concept known as ADMET. This acronym stands for Absorption, Distribution, Metabolism, Excretion, and Toxicity. These five processes determine how a drug moves through the body, how it is changed, and how it is eliminated, while also assessing potential harmful effects. ADMET properties are important for ensuring new medicines are safe and effective.
The Pillars of ADMET
Absorption
Absorption is the process by which a drug enters the bloodstream from its administration site, such as a swallowed pill or an injection. For orally administered drugs, this involves traversing the gastrointestinal tract and then passing through the liver before reaching the systemic circulation. Factors like the drug’s solubility and its permeability, or how easily it can pass through biological membranes, influence how much of the drug gets absorbed and how quickly. Small molecules cross membranes through passive transport or with the help of specialized drug transporter proteins.
Distribution
Once a drug enters the bloodstream, distribution describes its reversible movement to various tissues and organs. The extent and rate of this movement are influenced by factors such as blood flow, the drug’s ability to bind to proteins, and its tendency to accumulate in certain tissues. A drug’s lipophilicity, or its affinity for fats, and its molecular weight can affect how widely it distributes.
Metabolism
Metabolism refers to the chemical changes the body makes to a drug, primarily occurring in the liver. This process involves enzymes, such as cytochrome P450 (CYP) and UDP-glucuronosyltransferases (UGTs), which modify the drug’s structure. These modifications can activate an inactive drug (a “prodrug”) or break down the drug into metabolites, which are less active or easier for the body to excrete. Understanding metabolism helps predict potential drug interactions and side effects.
Excretion
Excretion is the body’s process of removing the drug and its metabolites. The main routes for elimination are through the kidneys, via urine, and through the liver, via bile and feces. Other routes include excretion through sweat, tears, or breath. The rate at which a drug is excreted directly impacts its half-life, influencing how frequently a drug needs to be administered to maintain its therapeutic effect.
Toxicity
Toxicity evaluates the potential harmful effects a drug can have on the body. This includes understanding side effects and more severe adverse reactions. Assessing toxicity involves identifying if the drug or its metabolites could damage organs or interfere with normal bodily functions. Poor ADMET properties, such as high concentrations of a drug or its metabolites accumulating in specific tissues, can lead to toxic effects.
Integrating ADMET into Drug Discovery
ADMET considerations are integrated throughout the drug discovery and development pipeline, rather than being a single, isolated assessment. This continuous evaluation helps guide decisions and reduce the risk of later-stage failures.
In the early stages of drug discovery, called the preclinical phase, ADMET properties are screened to rapidly evaluate many potential drug candidates. This initial screening utilizes in silico (computer-based) models to predict how compounds will behave, helping to filter out unsuitable compounds and prioritize promising ones. This approach saves time and resources by reducing the number of compounds that proceed to more costly experimental testing.
As promising compounds emerge, ADMET principles guide lead optimization. During this phase, chemists modify the chemical structure of potential drug candidates to enhance their ADMET profiles while maintaining or improving their therapeutic effect. The aim is to create a molecule with balanced properties that allow it to be absorbed, distributed, metabolized, and excreted predictably, with minimal toxicity.
Preclinical testing involves comprehensive ADMET studies, in animal models, to gather detailed pharmacokinetic and toxicity data. These in vivo studies provide insights into how the drug behaves in a living system, helping to predict its actions in humans. Data from these studies are used to estimate parameters like drug clearance, bioavailability, exposure, and half-life, which are important for regulatory submissions.
ADMET data also inform the design of clinical trials and patient safety monitoring. Information on how the drug is absorbed, distributed, metabolized, and excreted in humans, gathered during early clinical phases, helps determine appropriate dosing regimens and identify potential drug-drug interactions. This continuous assessment throughout development helps ensure the drug’s safety and effectiveness as it moves closer to patient use.
ADMET and Drug Outcomes
The ADMET profile of a drug candidate directly influences its success or failure in reaching patients. Poor ADMET characteristics are a major reason why many drug candidates do not make it to market. For example, if a drug is poorly absorbed into the bloodstream, it may not reach therapeutic concentrations at its target site, rendering it ineffective.
Similarly, if a drug is metabolized too quickly, it might be eliminated from the body before it has a chance to exert its desired effect, requiring impractically high doses. Conversely, if a drug is metabolized too slowly or accumulates in tissues, it could lead to prolonged exposure and increased risk of toxicity. Toxicity issues, including unexpected side effects or organ damage, account for a significant percentage of drug failures.
Optimized ADMET properties contribute to a drug’s effectiveness at the right dose, predictable action, and minimal side effects. A drug with a well-understood and favorable ADMET profile is more likely to be safe, well-tolerated, and effective. This balance means the drug can reach its target, stay in the body long enough to work, and be cleared without causing undue harm.
Developing drugs with balanced ADMET properties helps reduce the high attrition rate in the pharmaceutical industry, where only a small fraction of identified compounds become approved medicines. By identifying and addressing ADMET issues early, companies can avoid costly late-stage failures and increase the chances of bringing new, safe, and effective treatments to patients.