ADMET 2

ADMET is an acronym that stands for Absorption, Distribution, Metabolism, and Excretion. These are the key pharmacological processes critical for assessing drug action and efficacy.
Key Components:
- Absorption: The process of drug entry into the bloodstream.
- Distribution: The dissemination of the drug throughout the body's compartments.
- Metabolism: The biochemical modification of drugs by the body.
- Excretion: The elimination of drugs from the body.
Free Drug vs. Metabolites:
- Free Drug: The active form of the drug circulating in the body.
- Metabolites: The byproducts of drug metabolism, which can be either active or inactive.
Drug Targets:
- Active Targets: Sites where drugs exert their pharmacological effects.
- Inactive Targets: Sites that do not influence the drug's efficacy but may impact pharmacokinetics.
Drug Reservoirs:
- Free: Unbound drug available for action.
- Bound: Drug attached to proteins, which affects its activity and distribution.
Systemic Circulation: The pathway through which the drug circulates throughout the body.
Toxicity and Pharmacological Effect:
- Toxicity: Unwanted side effects of drugs, which can arise from both pharmacokinetic and pharmacodynamic interactions.
- Clinical Response: The measurable change in the condition being treated, influenced by pharmacodynamics and pharmacokinetics.

Mechanisms of Absorption:
- Factors that determine how well a drug is absorbed include route of administration, drug formulation, and physiological factors (e.g., pH, surface area).
- Prodrugs: Inactive drugs that become active only after metabolism, enhancing absorption.
- Absorption-based Drug-Drug Interactions (DDIs): Interactions where one drug affects the absorption of another, impacting efficacy and safety.
Routes/Sites of Administration: Include oral, intravenous, intramuscular, subcutaneous, transdermal, etc., which affect how quickly and effectively drugs enter circulation.

Models of Distribution: Mathematical models used to describe how drugs distribute in body compartments.
Volume of Distribution (Vd): A key pharmacokinetic measurement that indicates the extent of drug distribution throughout the body.
Sequestration: The process by which drugs accumulate in certain tissues or compartments, affecting their therapeutic levels in the bloodstream.
Blood-Brain Barrier (BBB) / Central Nervous System (CNS) Penetration: Factors influencing whether a drug can cross the BBB to act on CNS targets.
Distribution-based Drug-Drug Interactions: Occur when simultaneous administration of drugs affects their distribution in the body.

Sites of Metabolism: Organs where drug metabolism predominantly occurs, primarily the liver.
Influencing Factors: Factors such as age, genetic variability, enzyme activity, and presence of other substances can significantly affect drug metabolism rates.
Types of Chemical Reactions: Common reactions include oxidation, reduction, hydrolysis, and conjugation, which transform drugs into metabolites.
Metabolic Pathways and Enzymes: Understanding the enzymes involved in metabolism (e.g., cytochrome P450 family) is critical for predicting drug interactions and toxicity.
Metabolism-based Drug-Drug Interactions: Interactions that result from one drug influencing the metabolism of another drug, profoundly altering therapeutic outcomes.

Routes of Clearance: Mechanisms through which drugs are excreted, primarily through urine and bile.
Influencing Factors: Various physiological and pathological conditions can affect elimination rates, influencing drug safety and efficacy.

Learning Objectives:
- Define and differentiate terms associated with absorption.
- Compare passive diffusion and active transport mechanisms.
- Explain Fick's Law of Diffusion.
- List the major families of active transporters.

Definition: Describes the rate of diffusion of a substance across a membrane. The formula states: $ext{Flux} = rac{A imes P}{T} imes (C<em>2 - C</em>1)$
- Where:
- Flux = molecules crossing the membrane per unit time.
- A = area of the membrane.
- P = permeability coefficient of the membrane.
- T = thickness of the membrane.
- C2 - C1 = concentration difference across the membrane.

Overview: This is the major absorption mechanism for most drugs and biomolecules.
- The absorption rate is influenced by the following factors:
- Concentration Gradient: The difference in concentration across the membrane; higher gradients enhance absorption.
- Partition Coefficient (logP): Reflects drug lipophilicity; drugs with higher values tend to absorb better.
- Surface Area of Membrane: Larger surface areas facilitate increased absorption.
- pH & pKa: Ionizable drugs' absorption varies based on environmental pH in relation to their pKa.

Characteristics:
- Requires energy (ATP) for transport.
- Can move substances against an electrochemical gradient, often engaging in saturable kinetics;
- Often selective regarding substrates.
- Subject to competitive inhibition, where drugs may inhibit each other's transport.
Transporters:
- Solute Carrier (SLC) Superfamily: E.g., OATPs and POTs play crucial roles in drug absorption.
- ATP-Binding Cassette (ABC) Superfamily: Includes P-glycoprotein (PGP), MRP, and BCRP, which are involved in drug resistance and absorption processes.
Dual Functionality: Many transporters may facilitate both drug absorption and elimination, becoming potential drug targets.

Students should be able to:
- Define and differentiate absorption-related terms.
- Compare passive diffusion with active transport.
- Explain principles of Fick's Law of Diffusion and its application in drug absorption.
- Identify the key superfamilies of transporters relevant for pharmacology.