ADMET Overview
Absorption, Distribution, Metabolism, Elimination & Toxicology (ADMET)
Roger S. Armen, PhD
Department of Pharmaceutical Sciences
Jefferson College of Pharmacy
PHRM 513: Medicinal Chemistry
Date: January 23, 2026
Lecture Objectives
Understand how functional groups determine the physiochemical properties of drugs and the fate of a drug molecule in the body.
Understand the following concepts:
Acid/base properties and their effect on drug solubility and absorption.
LogP and its effects on drug solubility and absorption.
How LogP and degree of ionization influence drug administration and appropriate dosage forms.
Explain the significance of ADMET properties as they relate to drug action and therapeutic effects.
Introduction to Drug Action
Drug Action:
Resulting from interactions of the drug with enzymes, receptors, or other molecules in the body.
Degree of Drug Activity is influenced by:
Concentration of the drug in an aqueous solution in contact with target proteins or receptors.
Factors affecting drug concentration are classified as:
Pharmacokinetic (PK) Phase:
Involves the movement of the drug from administration site to its action site (Absorption, Distribution, Metabolism, Elimination - ADME).
Pharmacodynamic (PD) Phase:
Relates to the chemical relationship between the drug and its target, which impacts pharmacological activity.
Pharmacokinetics
Plasma Concentration vs. Time
Graph: Plasma Concentration of BAY XX-XXXX after 5 mg/kg oral administration to rats.
Cmax concentration peaks at higher levels over time.
Oral Absorption & First Pass Metabolism
Passage Mechanisms:
Involves movement through membranes via:
Passive diffusion
Active transport
Orally administered drugs:
A significant fraction is absorbed into portal vein blood and directed towards the liver, where drug metabolism occurs.
First Pass Metabolism:
A process where a considerable amount of the administered dose is metabolized during its first encounter with the liver.
Distribution in the Body
Factors affecting drug distribution include:
Solubility (absorption)
Membrane permeability (A, D)
Efflux transporters (A, D)
Drug metabolism and clearance (M, E)
Drug-drug interactions (E)
Drug toxicity (T)
Key Sites:
Liver (drug metabolism)
Renal Clearance (E)
Tissue protein binding (D)
Cell permeability (D)
CNS (Central Nervous System) drug target
Physiochemical Properties Related to Absorption
Important factors include:
Degree of ionization at a specific pH (pKa)
Lipid/water solubility (LogP & LogD)
Log P and Lipid Partition Coefficient
Experimental Approach:
Measure the partitioning of a drug between octanol and water.
Why Octanol?:
Mimics lipid membrane environments due to its polar head and hydrocarbon chain.
Log P is defined as:
Example: At equilibrium, ratios of molecules in lipid versus aqueous phases are described.
Practical Implications for Log P Values
Rules of thumb for Log P:
Optimal CNS penetration: Log P ≈ 2 ± 0.7
Optimal Oral absorption: Log P ≈ 1.8
Optimal Intestinal absorption: Log P ≈ 1.35
Optimal Colonic absorption: Log P ≈ 1.32
Optimal Sublingual absorption: Log P ≈ 5.5
Optimal Percutaneous absorption: Log P ≈ 2.6
Approximate ranges for Log P:
Low Log P (<0): Injectable medications
Medium Log P (0-3): Oral formulations
High Log P (3-4): Transdermal medications
Very High (4-7): Risks of toxic accumulation in fatty tissues.
Predicting LogP Based on Functional Groups
Empirical Approach Developed by Lemke:
Carbon-solubilizing potential (CSP) of organic functional groups (FGs) determines solubility.
A molecule is considered water soluble if the CSP of FGs exceeds the total number of carbon atoms in the molecule.
Example with glucose:
Contains 6 FGs including ethers and alcohols, leading to high CSP (17).
Thus, glucose is predicted to be very water soluble.
Carbon Solubilizing Potential of Organic Functional Groups
Water solubilizing potentials vary by functional group type in mono- or polyfunctional molecules:
Monofunctional Molecule Water Solubility:
Alcohol, Phenol: 5 to 6 carbons.
Ether, Ketone, Amine, Carboxylic Acid: 4 to 5 to 6 carbons.
Polyfunctional Molecule Water Solubility:
Alcohol, Amine, etc.: Typically require fewer carbons due to multiple FGs enhancing solubility.
Prediction of Water Solubility Example
Example with Anileridine (a narcotic analgesic):
Contains 3 functional groups:
Aromatic amine, tertiary alkyl amine, and ester (Total CSP = 9).
Total carbon atoms = 21 (CSP < N carbon atoms) indicates low water solubility (0.01% solubility reported in U.S. Pharmacopeia (USP)).
Physiochemical Properties and Absorption Factors
Factors include:
Degree of ionization (pKa)
Lipid/water solubility (LogP/LogD)
Molecular size (Molecular Weight)
Dosage formulation and concentration.
Dissolution requirement: transition from solid to aqueous state is key for absorption.
Membrane Permeability
Passive membrane diffusion involves:
Greater degree of ionization at specific pH increases absorption rates for neutral compounds compared to charged ones.
Increased LogP enhances membrane permeability.
Molecular weight significantly impacts permeability; lower MW means generally better permeability.
Dosage Formulation:
Dosage design may affect absorption through alterations in solid-state properties (e.g., particle size, excipients).
General Rules of Oral Absorption
Absorption primarily occurs in the small intestine due to:
Larger surface area and longer contact time compared to the stomach.
Greater permeability of intestinal membranes than gastric mucosal layers.
Gastric Emptying:
Often rate-limiting factor for absorption, influenced by food intake (e.g., fatty foods slow gastric emptying).
Stomach pH varies (1.4 to 8 across sections).
Drug Absorption Mechanisms
Passage from administration site into plasma occurs via:
Routes including injection, oral, rectal, sublingual.
Mechanisms include:
Passive diffusion, active transport, endocytosis, exocytosis.
Non-Oral Routes of Administration
Topical/Transdermal:
Few drugs can penetrate skin effectively.
Sublingual:
Avoids first-pass metabolism through venous drainage into the superior vena cava.
Rectal:
~50% of the drug bypasses the liver, reducing first-pass metabolism.
Pulmonary:
Instantaneous absorption, avoids first-pass metabolism.
Parenteral:
Includes injection types: subcutaneous, intramuscular, intraperitoneal, intravenous.
Desirable Drug Properties
Essential properties include:
Adequate solubility & absorption (A)
Sufficient concentration in target tissues (D)
Appropriate metabolic stability & low toxic metabolite formation (T)
Extensive interaction with intended targets (D)
Minimal interaction with unintended targets (T)
Minimized interaction with co-administered drugs (M, T)
Minimal toxicity (T) and appropriate elimination rates (E)
ADMET properties are crucial for clinical success and optimal drug candidate selection.
Lipinski’s “Rule of Five”
Guidelines for drug-like small molecules:
Molecular Weight (MW) < 500 daltons
Calculated LogP < 5
Minor rules include:
≤ 5 hydrogen bond donors (e.g., N-H or O-H)
≤ 10 hydrogen bond acceptors (e.g., carbonyl groups, O, N, S).
Exceptions exist for drugs acting as biological transporter substrates.
Oral absorption: Requires a balance between drug solubility and membrane permeability.
Drug Distribution
Transportation from administration site to action site primarily occurs through:
Blood circulation (major)
Lymphatic system (minor)
Drugs are distributed quickly to all body areas accessible by blood.
Implications:
Chemical and physical properties of blood influence drug concentration at action sites.
Drug Transport & Plasma Proteins
Drugs may exist in blood as free entities or bound to plasma proteins (mostly reversible).
Equilibrium:
Bound drugs have no pharmacological effect until released.
Displacement Implications:
One drug may displace another if it binds more stably to plasma proteins, affecting drug efficacy and interactions.
Major Plasma Proteins in Drug Binding
Serum Albumin:
Binds to acidic and neutral drugs, predominant serum protein.
Alpha-1 Acid Glycoprotein:
Binds to basic drugs.
Other Proteins:
Lipoproteins and a, b, g-globulins also play a role.
Role of Drug Transporters
Transporters facilitate drug passage from the gut to circulation and regulate drug movement in/out of the liver and kidneys.
Key transport mechanisms:
Passive diffusion and active transport via transporters, endocytosis, and exocytosis.
Different Drug Transporters
In the Gastrointestinal Tract:
P-glycoprotein (P-gp): Transports several CYP3A4 substrates.
Multidrug resistance proteins (MRP2, MRP4): Highly expressed in the small intestine.
Peptide transporter 1 (PEPT1): Transports di- and tri-peptides and drugs mimicking amino acids.
Organic ion transporters (OATP, OAT, OCT): Responsible for various drug movements.
Drug Metabolism
Refers to the biological transformation of drug molecules into metabolites for excretion (usually via urine).
Functions of Drug Metabolism:
Typically detoxifies and increases water solubility of drugs.
Can also lead to increased toxicity, activation, or deactivation of biological activity.
Primary site of metabolism: liver, but can also occur in other locations (e.g., kidneys, lungs, etc.).
Xenobiotics:
Any foreign substance to the body can undergo metabolism, making this a key consideration in drug development.
Drug Metabolism & Elimination
Relationship between Liver & Kidney
Primary excretion routes include:
Kidneys (via glomerular filtration or tubular secretion).
Other excretion forms: feces and minimal other forms (sweating, exhalation).
Example:
Thalidomide use during pregnancy led to drug-induced malformations in neonates (teratogenesis).
Drug Elimination
Involves removal of active drug forms from the body:
Via metabolism and all forms of excretion.
Reduces concentrations at action sites, affecting therapeutic effects.
Slow Elimination Advantages:
May reduce required dosing and decrease side effects.
Risks of Slow Elimination:
Potential drug deposition in tissues and increased toxicity risks.
Rapid Elimination:
May require increased dosing and raise risks of side effects.
Rate of Elimination:
A critical factor in drug design and development.