Fiche de révision : Fundamentals of Drug Absorption and Metabolism

📋 Course Outline

1. Drug Absorption Mechanisms
2. Factors Affecting Absorption
3. Volume of Distribution
4. Protein Binding Effects
5. Blood-Brain Barrier
6. Drug Metabolism Phases
7. Metabolic Enzyme Systems
8. Factors Influencing Metabolism
9. Routes of Excretion
10. Renal Excretion Processes
11. Hepatic Excretion
12. Pharmacokinetic Models

📖 1. Drug Absorption Mechanisms

🔑 Key Concepts & Definitions

• Passive Diffusion: Movement of drug molecules across cell membranes from an area of higher to lower concentration without energy, primarily influenced by lipophilicity and ionization state.

• Facilitated Diffusion: Carrier-mediated transport that allows molecules to cross membranes along their concentration gradient without energy expenditure, often specific to certain drugs.

• Active Transport: Energy-dependent process where drugs are transported against their concentration gradient via carrier proteins, affecting absorption especially for nutrients and some drugs.

• Endocytosis: Cellular process where the cell engulfs external substances into vesicles, allowing for absorption of larger molecules or particles.

• Bioavailability (F): The proportion of an administered dose that reaches systemic circulation unchanged, influenced by absorption and first-pass metabolism.

• Ionization & pH: The degree to which a drug is ionized depends on pH; non-ionized forms are generally more lipophilic and absorbed more readily, especially for weak acids and bases.

📝 Essential Points

• Absorption mechanisms determine how quickly and efficiently a drug enters systemic circulation, impacting onset of action.

• Passive diffusion is the predominant mechanism for most drugs, especially those that are lipophilic; it depends on concentration gradients and membrane permeability.

• Facilitated diffusion and active transport are significant for certain drugs, especially those mimicking endogenous substrates or requiring specific transporters.

• Endocytosis is less common but important for large molecules like peptides and proteins.

• Factors such as pH, surface area (e.g., intestines vs. stomach), blood flow, and drug formulation influence absorption efficiency.

• The extent of absorption is quantified by bioavailability; oral drugs often have less than 100% due to incomplete absorption and first-pass metabolism.

💡 Key Takeaway

Understanding the mechanisms of drug absorption—primarily passive diffusion, facilitated diffusion, and active transport—along with factors affecting them, is essential for predicting drug onset, optimizing delivery routes, and designing effective dosing regimens.

📖 2. Factors Affecting Absorption

🔑 Key Concepts & Definitions

• Bioavailability: The proportion of an administered drug that reaches systemic circulation unchanged; influenced by absorption and first-pass metabolism.
• pH and Ionization: The acidity or alkalinity of the environment affects drug ionization; non-ionized forms are generally more lipid-soluble and absorbed more readily.
• Surface Area: The extent of the absorptive surface (e.g., intestinal mucosa) impacts the rate and extent of drug absorption; larger surface areas facilitate better absorption.
• Blood Flow: Increased blood flow at the absorption site enhances drug uptake by maintaining a concentration gradient.
• Formulation Factors: The physical form (tablet, liquid, capsule) and excipients influence dissolution and absorption rates.
• Lipid Solubility: Drugs with higher lipid solubility cross cell membranes more easily, increasing absorption efficiency.

📝 Essential Points

• Absorption mechanisms include passive diffusion, facilitated diffusion, active transport, and endocytosis; passive diffusion is predominant for most drugs.
• The pKa of a drug and the pH of the absorption site determine the degree of ionization, affecting membrane permeability.
• Drugs are better absorbed in their non-ionized form; thus, weak acids are absorbed in acidic environments, while weak bases favor alkaline conditions.
• Factors like food, gastrointestinal motility, and presence of other drugs can modify absorption; for example, food can delay gastric emptying or alter pH.
• The first-pass effect (metabolism in the gut wall and liver) can significantly reduce bioavailability, especially for oral drugs.

💡 Key Takeaway

Absorption of drugs is a complex process influenced by physiological, chemical, and formulation factors; understanding these helps optimize drug delivery and therapeutic effectiveness.

📖 3. Volume of Distribution

🔑 Key Concepts & Definitions

• Volume of Distribution (Vd): A theoretical volume that relates the amount of drug in the body to its plasma concentration; indicates how extensively a drug distributes into tissues relative to plasma.
• Vd Formula: ( V_d = \frac{\text{Amount of drug in body}}{\text{Plasma drug concentration}} ). It is expressed in liters (L).
• High Vd: Suggests extensive distribution into tissues and compartments outside the plasma, often seen with lipophilic drugs.
• Low Vd: Indicates limited distribution, with most drug remaining in the plasma, typical of hydrophilic or protein-bound drugs.
• Implication of Vd: Influences loading dose calculations and helps predict drug distribution characteristics.

📝 Essential Points

• Vd is a not actual physical volume but a conceptual parameter used to understand drug distribution.
• Drugs with a large Vd (e.g., digoxin, diazepam) tend to accumulate in tissues, prolonging their effects.
• Drugs with a small Vd (e.g., aminoglycosides) remain mostly in the bloodstream, making them easier to eliminate.
• Changes in Vd can occur due to physiological factors such as edema, dehydration, or alterations in body fat and plasma protein levels.
• Understanding Vd helps in determining appropriate loading doses to quickly achieve desired plasma concentrations.

💡 Key Takeaway

Volume of distribution is a crucial pharmacokinetic parameter that reflects how a drug disperses within the body, guiding dosing strategies and predicting drug behavior based on tissue affinity and plasma binding.

📖 4. Protein Binding Effects

🔑 Key Concepts & Definitions

• Protein Binding: The reversible attachment of drugs to plasma proteins (mainly albumin), which influences the drug's distribution, free (active) concentration, and elimination.
• Free (Unbound) Drug: The fraction of a drug not bound to plasma proteins; pharmacologically active and capable of crossing membranes, exerting therapeutic effects, and being metabolized or excreted.
• Bound Drug: The portion of a drug attached to plasma proteins; generally inactive and serves as a reservoir, releasing free drug as plasma levels decline.
• Displacement: The process where one drug displaces another from plasma protein binding sites, increasing free drug concentration and potentially causing toxicity.
• Protein Binding Percentage: The proportion of the total drug in plasma that is bound to proteins; high binding (>90%) indicates most of the drug is bound, affecting distribution and clearance.

📝 Essential Points

• Protein binding affects the distribution and half-life of drugs; only unbound drugs are available for therapeutic action and elimination.
• Drugs with high protein binding can compete for binding sites, leading to drug interactions that alter free drug levels.
• Displacement interactions can cause transient increases in free drug levels, risking toxicity, especially with drugs like warfarin, phenytoin, and diazepam.
• Changes in plasma protein levels (e.g., hypoalbuminemia in liver disease, malnutrition, or critical illness) can increase free drug concentrations, necessitating dose adjustments.
• The extent of protein binding influences the volume of distribution (Vd); highly bound drugs tend to have a lower Vd, remaining largely within the plasma.

💡 Key Takeaway

Protein binding modulates drug activity, distribution, and clearance; understanding its dynamics is essential for predicting drug interactions and adjusting dosages to ensure safety and efficacy.

📖 5. Blood-Brain Barrier

🔑 Key Concepts & Definitions

• Blood-Brain Barrier (BBB): A highly selective, semipermeable border formed by endothelial cells lining cerebral microvessels, which restricts the passage of substances from the bloodstream into the brain tissue.
• Endothelial Cells: Cells lining blood vessels; in the BBB, these are tightly joined by tight junctions, limiting paracellular transport.
• Tight Junctions: Specialized connections between endothelial cells that prevent the free passage of molecules, maintaining BBB integrity.
• Transport Mechanisms: Processes allowing specific molecules to cross the BBB, including passive diffusion, carrier-mediated transport, and receptor-mediated transcytosis.
• Lipophilicity: The affinity of a substance for lipid environments; highly lipophilic drugs cross the BBB more easily.
• Efflux Pumps: Transport proteins such as P-glycoprotein that actively expel certain drugs and toxins from the brain back into the bloodstream, limiting drug accumulation.

📝 Essential Points

• The BBB protects the brain from toxins and pathogens but also limits drug delivery, complicating treatment of CNS disorders.
• Lipophilic, small, and uncharged molecules cross the BBB more readily via passive diffusion.
• Hydrophilic or large molecules require specialized transport mechanisms (e.g., glucose transporter for glucose, amino acid transporters).
• Efflux pumps like P-glycoprotein actively remove many drugs, reducing their CNS penetration.
• The integrity of the BBB can be compromised in pathological states such as inflammation, trauma, or tumors, affecting drug permeability.
• Many CNS-active drugs are designed to exploit transport mechanisms or possess high lipophilicity to enhance crossing.

💡 Key Takeaway

The blood-brain barrier is a complex, protective interface that selectively regulates substance entry into the brain, posing both challenges and opportunities for CNS drug delivery.

📖 6. Drug Metabolism Phases

🔑 Key Concepts & Definitions

• Drug Metabolism: The biochemical process by which the body transforms lipophilic drugs into more hydrophilic compounds for easier excretion.
• Phase I Reactions: Metabolic reactions involving oxidation, reduction, or hydrolysis that introduce or expose functional groups on the drug molecule.
• Cytochrome P450 Enzymes: A family of heme-containing enzymes primarily located in the liver responsible for catalyzing many Phase I oxidation reactions.
• Phase II Reactions: Conjugation reactions where the drug or its Phase I metabolite is linked to endogenous molecules (e.g., glucuronic acid, sulfate) to increase water solubility.
• First-Pass Metabolism: The initial hepatic metabolism of a drug following oral administration, which can significantly reduce bioavailability.
• Prodrugs: Inactive compounds that require metabolic activation (often via Phase I or II reactions) to become pharmacologically active.

📝 Essential Points

• Drug metabolism occurs mainly in the liver but also in other tissues like the intestines and kidneys.
• Phase I reactions often prepare drugs for Phase II by introducing reactive groups, but some drugs are excreted unchanged.
• Cytochrome P450 enzymes exhibit genetic polymorphisms, leading to variability in drug metabolism among individuals.
• Phase II conjugation reactions generally lead to inactive, water-soluble metabolites that are readily excreted.
• The rate of metabolism influences drug half-life, dosing intervals, and potential for drug interactions.
• Inducers (e.g., rifampin) increase enzyme activity, accelerating drug clearance; inhibitors (e.g., ketoconazole) decrease enzyme activity, prolonging drug action.
• Understanding metabolism is crucial for predicting drug interactions, individual responses, and designing appropriate dosing regimens.

💡 Key Takeaway

Drug metabolism transforms lipophilic drugs into hydrophilic metabolites through enzyme-mediated reactions, primarily in the liver, which is essential for drug elimination and influences therapeutic efficacy and safety.

📖 7. Metabolic Enzyme Systems

🔑 Key Concepts & Definitions

• Cytochrome P450 Enzymes (CYPs): A large family of heme-containing enzymes primarily located in the liver that catalyze oxidation reactions during Phase I drug metabolism, playing a central role in the biotransformation of many drugs.
• Phase I Reactions: Metabolic processes involving oxidation, reduction, or hydrolysis that introduce or expose functional groups on drugs, often making them more polar and ready for Phase II conjugation.
• Phase II Reactions: Conjugation processes where the drug or its Phase I metabolite is linked to endogenous molecules (e.g., glucuronic acid, sulfate) to increase water solubility for excretion.
• Enzyme Induction: The process by which certain drugs or chemicals increase the activity or amount of metabolic enzymes (e.g., CYPs), leading to faster drug metabolism.
• Enzyme Inhibition: The process where drugs or substances decrease enzyme activity, resulting in slower metabolism of substrates and potentially increased drug levels.
• Genetic Polymorphisms: Variations in genes encoding metabolic enzymes that lead to differences in enzyme activity among individuals, affecting drug efficacy and toxicity.

📝 Essential Points

• The liver's cytochrome P450 enzyme system is the primary pathway for drug metabolism, affecting drug clearance and half-life.
• Phase I reactions often produce metabolites that are more reactive or less active, but sometimes toxic; Phase II reactions typically detoxify these metabolites.
• Enzyme induction (e.g., by rifampin) accelerates drug metabolism, potentially reducing drug efficacy, while enzyme inhibition (e.g., by ketoconazole) can cause drug accumulation and toxicity.
• Genetic polymorphisms in enzymes like CYP2D6, CYP2C19, and CYP2C9 lead to classifications such as poor, intermediate, extensive, or ultra-rapid metabolizers, influencing individual responses.
• Drug interactions frequently involve enzyme modulation, necessitating dose adjustments or alternative therapies to prevent adverse effects.
• Factors such as age, liver function, and concomitant medications significantly influence enzyme activity and drug metabolism.

💡 Key Takeaway

Metabolic enzyme systems, especially the cytochrome P450 family, are crucial in determining drug clearance and response; understanding their regulation, genetic variability, and potential for interaction is essential for safe and effective pharmacotherapy.

📖 8. Factors Influencing Metabolism

🔑 Key Concepts & Definitions

• Enzyme Induction: The process by which certain drugs or substances increase the activity or quantity of metabolic enzymes, leading to faster drug metabolism and decreased plasma drug levels.
• Enzyme Inhibition: The process where substances decrease enzyme activity, resulting in slower drug metabolism and potentially increased drug concentrations.
• Genetic Polymorphism: Variations in DNA sequence among individuals that affect enzyme activity, leading to differences in drug metabolism rates (e.g., fast vs. slow metabolizers).
• Age-Related Changes: Alterations in metabolic capacity due to age, typically decreased in neonates and the elderly, affecting drug clearance.
• Drug-Drug Interactions: When one drug affects the metabolism of another, either by inducing or inhibiting metabolic enzymes, impacting drug efficacy and toxicity.
• Liver Function: The health and capacity of the liver influence metabolic rate; impaired liver function can reduce drug metabolism.

📝 Essential Points

• Enzyme induction (e.g., by rifampin) accelerates metabolism, often reducing drug effectiveness.
• Enzyme inhibition (e.g., by cimetidine) slows metabolism, increasing risk of toxicity.
• Genetic polymorphisms can categorize individuals as poor, intermediate, extensive, or ultra-rapid metabolizers, influencing dosing.
• Age impacts metabolism: neonates have immature enzyme systems, while elderly may have reduced hepatic blood flow and enzyme activity.
• Drug interactions are critical; for example, erythromycin inhibits CYP3A4, affecting drugs metabolized by this enzyme.
• Liver diseases (cirrhosis, hepatitis) decrease metabolic capacity, necessitating dose adjustments.

💡 Key Takeaway

Metabolism is highly influenced by genetic, physiological, and environmental factors, which can significantly alter drug clearance and therapeutic outcomes. Understanding these factors is essential for personalized medication management.

📖 9. Routes of Excretion

🔑 Key Concepts & Definitions

• Excretion: The biological process of eliminating waste substances and drugs from the body, primarily via the kidneys or liver.
• Renal Excretion: The removal of substances through the kidneys, involving filtration, secretion, and reabsorption into urine.
• Hepatic Excretion: The elimination of drugs via metabolism in the liver followed by excretion into bile and feces.
• Biliary Excretion: The process where drugs or their metabolites are secreted into bile by the liver and eliminated through feces.
• Enterohepatic Circulation: The recycling of drugs or metabolites between the intestine and liver via bile, prolonging drug action.
• Other Routes: Minor excretion pathways include exhalation (lungs), sweat, saliva, and breast milk.

📝 Essential Points

• The primary route of drug excretion is renal, involving glomerular filtration, tubular secretion, and reabsorption, which collectively determine drug clearance.
• Lipid-soluble drugs tend to be reabsorbed in the renal tubules, reducing excretion, whereas water-soluble drugs are excreted more readily.
• Hepatic excretion involves drug metabolism into more water-soluble forms, facilitating elimination via bile and feces.
• Biliary excretion can lead to enterohepatic recirculation, which may cause prolonged drug effects or re-exposure.
• The efficiency of excretion influences drug half-life and dosing intervals; impaired excretion (e.g., in renal failure) necessitates dose adjustments.
• Monitoring renal function (e.g., serum creatinine, GFR) is critical for drugs with significant renal clearance to prevent toxicity.

💡 Key Takeaway

Excretion, primarily via the kidneys and liver, is essential for removing drugs and their metabolites; understanding these routes allows for proper dosing adjustments and minimizes toxicity, especially in cases of organ impairment.

📖 10. Renal Excretion Processes

🔑 Key Concepts & Definitions

• Renal Excretion: The process by which the kidneys eliminate drugs and their metabolites from the bloodstream into the urine.
• Glomerular Filtration: The passive process where plasma water and small molecules, including unbound drugs, are filtered through the glomeruli into Bowman's capsule.
• Tubular Secretion: Active transport mechanism that moves drugs from peritubular capillaries into the renal tubules for excretion.
• Tubular Reabsorption: The process by which some substances, especially lipid-soluble drugs, are reabsorbed from the renal tubules back into the bloodstream.
• Creatinine Clearance: A clinical measure used to estimate the glomerular filtration rate (GFR), reflecting kidney function and drug clearance capacity.
• Half-life (t1/2) in Renal Excretion: The time required for the plasma concentration of a drug to reduce by half due to renal elimination.

📝 Essential Points

• Primary Route: Renal excretion is the main pathway for eliminating many drugs and their metabolites, especially hydrophilic compounds.
• Filtration: Only unbound (free) drugs are filtered at the glomerulus; protein-bound drugs are not filtered.
• Secretion and Reabsorption: Active secretion can increase drug clearance, while reabsorption, especially of lipophilic drugs, can prolong drug presence.
• Factors Affecting Renal Excretion:
  • Renal Function: Impaired kidney function (e.g., in renal failure) reduces drug clearance, necessitating dose adjustments.
  • pH of Urine: Altering urine pH can influence drug ionization and reabsorption; for example, alkalinization can enhance excretion of weak acids.
  • Drug Properties: Molecular size, lipophilicity, and protein binding influence renal elimination.
• Clinical Relevance:
  • Monitoring renal function (via creatinine clearance) guides dosing.
  • Some drugs are designed for renal excretion to minimize systemic toxicity.
  • Renal impairment prolongs drug half-life, increasing risk of toxicity.

💡 Key Takeaway

Renal excretion is a vital process for drug elimination, heavily influenced by kidney function and drug properties; understanding this process is essential for appropriate dosing and avoiding toxicity, especially in patients with renal impairment.

📖 11. Hepatic Excretion

🔑 Key Concepts & Definitions

• Hepatic Excretion: The process by which drugs and their metabolites are eliminated from the body via the liver into bile, eventually reaching the gastrointestinal tract for elimination.
• Biliary Secretion: The transport of drugs or their metabolites from hepatocytes into bile, often involving active transport mechanisms.
• Enterohepatic Recirculation: The recycling of drugs or metabolites between the liver and intestines via biliary excretion and reabsorption, prolonging drug action.
• Phase II Metabolites: Water-soluble conjugates formed during hepatic metabolism (e.g., glucuronides, sulfates) that are more readily excreted into bile.
• Transport Proteins: Specific carriers (e.g., P-glycoprotein, MRPs) that facilitate the movement of drugs/metabolites into bile.
• Factors Affecting Hepatic Excretion: Liver function, drug polarity, molecular size, and transporter activity influence biliary excretion efficiency.

📝 Essential Points

• Hepatic excretion primarily involves the secretion of drug metabolites into bile, which then passes into the gastrointestinal tract for elimination.
• Lipophilic drugs are often metabolized into more hydrophilic conjugates (Phase II), enhancing biliary excretion.
• Enterohepatic recirculation can cause a secondary peak in plasma drug levels, affecting drug duration and dosing.
• Transport proteins like P-glycoprotein actively pump drugs into bile, influencing drug clearance and resistance.
• Liver impairment can reduce biliary excretion, leading to drug accumulation and toxicity.
• Some drugs are designed to undergo hepatic excretion intentionally (e.g., certain antibiotics), while others are affected inadvertently.

💡 Key Takeaway

Hepatic excretion, through biliary secretion and enterohepatic recirculation, plays a crucial role in drug elimination, with transport proteins and liver function significantly influencing drug clearance and duration of action.

📖 12. Pharmacokinetic Models

🔑 Key Concepts & Definitions

• Pharmacokinetic Model: A mathematical representation of how drugs move through the body, simplifying complex biological processes to predict drug concentrations over time.
• One-Compartment Model: Assumes the body acts as a single, uniform compartment where the drug distributes instantaneously and evenly; used for drugs with rapid distribution.
• Multi-Compartment Model: Considers the body as multiple interconnected compartments (e.g., central and peripheral), accounting for different rates of drug distribution and elimination.
• Rate Constants (k): Parameters that describe the speed of drug transfer between compartments or elimination from the body; typically expressed as first-order rate constants.
• Half-life (t₁/₂): The time required for the drug concentration in plasma to decrease by 50%; influenced by the volume of distribution and clearance.
• Vd (Volume of Distribution): A theoretical volume indicating how extensively a drug distributes into body tissues relative to plasma concentration.

📝 Essential Points

• Pharmacokinetic models simplify drug behavior, aiding in dose calculation and understanding drug dynamics.
• The one-compartment model is suitable for drugs that rapidly equilibrate with tissues, providing straightforward calculations.
• The multi-compartment model is more accurate for drugs with complex distribution patterns, such as those accumulating in tissues.
• Rate constants determine the speed of distribution and elimination; they are essential for calculating half-life and dosing intervals.
• Understanding the relationship between Vd, clearance, and half-life helps predict how long a drug stays in the system and informs dosing schedules.
• These models are fundamental in clinical pharmacokinetics for designing appropriate dosing regimens, especially for drugs with narrow therapeutic windows.

💡 Key Takeaway

Pharmacokinetic models, whether one- or multi-compartment, provide a simplified yet powerful framework to predict drug concentrations over time, guiding safe and effective medication management.

📊 Synthesis Tables

⚠️ Common Pitfalls & Confusions

1. Confusing passive diffusion with facilitated diffusion; passive does not require carriers or energy.
2. Overlooking the impact of pH and ionization on drug absorption; non-ionized forms are more lipophilic.
3. Assuming high protein binding always reduces toxicity; displacement interactions can transiently increase free drug.
4. Misinterpreting volume of distribution as a physical volume; it's a theoretical parameter.
5. Ignoring first-pass metabolism's effect on bioavailability, especially for oral drugs.
6. Believing all drugs cross the blood-brain barrier equally; lipophilicity and transport mechanisms influence permeability.
7. Overestimating the significance of absorption mechanisms without considering physiological factors like blood flow or formulation.

✅ Exam Checklist

• Describe the main drug absorption mechanisms and their characteristics.
• Explain how pH and ionization influence drug absorption.
• Identify factors that affect the rate and extent of drug absorption.
• Define volume of distribution and interpret its clinical significance.
• Understand how protein binding affects drug distribution, activity, and clearance.
• Discuss the structure and function of the blood-brain barrier.
• Outline the phases of drug metabolism and key enzymes involved.
• Recognize factors influencing hepatic and renal drug metabolism.
• Describe routes of drug excretion and the processes involved in renal excretion.
• Differentiate between hepatic and renal excretion pathways.
• Summarize pharmacokinetic models and their applications.
• Recall the impact of physiological changes on drug absorption, distribution, metabolism, and excretion.