Introduction to ADME in Pharmacology

Introduction to ADME

• ADME stands for Absorption, Distribution, Metabolism, and Excretion
• ADME is a crucial concept in pharmacology, influencing drug action and safety

Objectives

• Describe the relationship between the dose-response curve and therapeutic index
• Compare and contrast various routes of drug administration on onset, intensity, and duration of effect
• Describe the first-pass effect and its impact on bioavailability
• Describe factors affecting drug absorption
• Describe factors affecting drug distribution
• Describe the consequences of drug metabolism
• Recognize the roles of phase I and phase II drug metabolizing processes
• Describe the roles of filtration, secretion, and reabsorption in renal excretion of drugs
• Predict drug excretion routes based on molecular properties
• Describe the relationship between drug elimination and steady-state drug levels

Key Terms

• Pharmacology: the study of substances interacting with living systems through chemical processes
• Drug: a substance that alters a biologic function
• Pharmacokinetics (PK): the process of drug absorption, distribution, metabolism, and excretion (ADME) in the body
• Pharmacodynamics (PD): the action or effects of bioactive substances on living organisms

Absorption, Distribution, Metabolism, & Excretion

• Absorption: the process of a substance entering the blood circulation
• Distribution: the dispersion or dissemination of a substance through bodily fluids and tissues
• Metabolism: the irreversible transformation of a parent compound into daughter metabolites
• Excretion: the removal of substances from the body

The Core of ADME

• Active drug needs sufficient levels and duration at the drug target (receptor) to modify biological response
• Biological response varies between individuals
• Understanding pharmacokinetics/pharmacodynamics is crucial for dose adjustment

Dose-Response Curve

• Shows the relationship between drug dose (x-axis) and response (y-axis)
• A minimum dose is needed before significant response occurs
• Response increases with dose until a plateau is reached
• Variability and slope indicate the range and speed of response changes with increased dose
• Potency and maximal effect are described by the curve

Therapeutic Index

• Therapeutic index (TI): the range of doses where a medication is effective without unacceptable adverse effects
• TI is determined by quantal dose-response curves
• Therapeutic window: clinically useful range between the minimum effective and minimum toxic doses

First Pass Metabolism

• Drugs absorbed via the GI tract enter the portal vein and pass through the liver before reaching systemic circulation
• Liver metabolism can reduce drug bioavailability (first-pass effect)

Distribution

• The movement of a drug from the bloodstream to various body compartments
• Factors affecting drug distribution include tissue permeability, blood flow, and binding to plasma proteins

Protein Binding

• Albumin, β-globulin, and α-acid glycoprotein are important plasma proteins involved in drug binding
• Bound drugs are inactive
• Amount of bound drug depends on free drug concentration, protein concentration, and binding site affinity
• Factors affecting protein binding (e.g., malnutrition) might impact drug concentrations

Apparent Volume of Distribution (Vd)

• Represents the apparent volume required to contain the total amount of drug in the body at a given concentration
• Vd can be larger than the physical volume of the body, indicating extensive tissue distribution

Metabolism (Biotransformation)

• Metabolism refers to the transformation of a drug through chemical reactions
• The goal is to enhance elimination, which frequently involves increased water solubility
• Phase I reactions (e.g., oxidation, reduction, hydrolysis) modify the drug structure
• Phase II reactions (e.g., glucuronidation, acetylation, sulfation) typically conjugate the drug with endogenous molecules, creating more water-soluble metabolites

Phase I Metabolism

• Adds a handle for larger, more water-soluble compounds to attach
• Includes oxidation, reduction, hydrolysis
• Enzymes catalyze these reactions

Phase II Metabolism

• Often referred to as conjugation reactions
• Phase I metabolites are conjugated to endogenous molecules, increasing water solubility and facilitating excretion
• Conjugation makes the molecular structure more polar, allowing for easier excretion

Excretion

• Removes unchanged drug from the body and prevents accumulation
• The liver and kidneys are primary sites of excretion
• Drug metabolism is a crucial step in excretion
• Metabolites are frequently charged and hydrophilic (water soluble)

Renal vs. Biliary Excretion

• Renal excretion: excretion into urine via glomerular filtration, active secretion, and passive reabsorption
• Hepatic/Biliary excretion: excretion into bile via diffusion and active transport

Renal Drug Excretion

• Many drugs are excreted unchanged
• Metabolites can also be excreted, depending on their properties
• Three key transport mechanisms: glomerular filtration, tubular secretion, and tubular reabsorption

Kidney and Nephron

• Kidneys are primary organs for excretion
• Nephrons are functional units of kidneys with specialized structures for filtration and reabsorption

Glomerular Filtration

• Non-selective process that filters small drugs based on size, charge, and shape

Tubular Secretion

• Active transport of large or ionized molecules that allows high concentration in urine

Tubular Reabsorption

• Passive diffusion; small, neutral, lipophilic molecules

Biliary Drug Excretion

• Drugs enter hepatocytes and are secreted into bile for elimination
• Conjugation (Phase II metabolism) often increases biliary excretion
• Excretion occurs in the bile, which then enters the digestive tract and is eliminated with feces

Summary of Questions and Answers

• No questions are provided in the slides.