2.1 Absorption

Absorption is a crucial process in toxicology that determines how substances enter the body and interact with target sites. This topic explores the factors affecting absorption, including physicochemical properties, biological factors, and routes of exposure.

The mechanisms of absorption, such as passive diffusion and active transport, are examined. The notes also cover absorption across barriers like the gastrointestinal tract and skin, as well as bioavailability and its importance in toxicology.

Factors affecting absorption

• Absorption is a crucial process in toxicology that determines the extent to which a substance enters the body and becomes available for interaction with target sites
• The rate and extent of absorption are influenced by various physicochemical properties of the substance, biological factors of the organism, and the route of exposure

Physicochemical properties

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• Lipophilicity: Substances with higher lipophilicity (octanol-water partition coefficient) tend to be absorbed more readily across biological membranes (benzene, PCBs)
• Molecular size and shape: Smaller molecules and those with more compact shapes generally have higher absorption rates compared to larger or bulkier molecules (ethanol vs. proteins)
• Ionization: The degree of ionization affects the absorption of a substance, with non-ionized forms typically being more readily absorbed than ionized forms (weak acids and bases)
• Solubility: Water-soluble substances are more easily absorbed in the gastrointestinal tract, while lipid-soluble substances are better absorbed through the skin and lungs (glucose vs. vitamin A)

Biological factors

• Species differences: Absorption rates and extents can vary among different species due to anatomical and physiological differences (rodents vs. humans)
• Age: The absorption of substances may differ between young and adult organisms due to variations in organ development and function (neonates vs. adults)
• Health status: Certain diseases or conditions can alter the absorption of substances by affecting the integrity of barriers or the function of transport systems (inflammatory bowel disease, malnutrition)
• Genetic factors: Genetic variations in transport proteins or enzymes involved in absorption can influence the uptake of substances (polymorphisms in P-glycoprotein)

Route of exposure

• Oral: Substances ingested orally are absorbed primarily in the small intestine, with factors such as pH, food intake, and gastrointestinal transit time influencing absorption (pharmaceuticals, food contaminants)
• Inhalation: Substances inhaled into the lungs are rapidly absorbed across the alveolar-capillary membrane, with particle size and solubility affecting absorption (volatile organic compounds, airborne particulates)
• Dermal: Absorption through the skin depends on factors such as skin integrity, hydration, and the presence of enhancers or barriers (topical medications, occupational exposures)
• Injection: Substances administered via injection (intravenous, intramuscular, subcutaneous) bypass absorption barriers and enter the systemic circulation directly (vaccines, drugs of abuse)

Mechanisms of absorption

• Absorption involves the movement of substances across biological membranes, which can occur through various mechanisms depending on the properties of the substance and the characteristics of the membrane
• Understanding the mechanisms of absorption is essential for predicting the uptake and distribution of toxicants in the body

Passive diffusion

• Passive diffusion is the movement of substances across membranes down their concentration gradient without the expenditure of energy
• Lipophilic substances readily diffuse across cell membranes, as they can partition into the lipid bilayer (oxygen, carbon dioxide, steroid hormones)
• Fick's law describes the rate of passive diffusion, which is proportional to the concentration gradient and the diffusion coefficient of the substance
• Factors influencing passive diffusion include the concentration gradient, membrane permeability, and surface area available for diffusion

Facilitated diffusion

• Facilitated diffusion involves the transport of substances across membranes by carrier proteins, without the use of energy
• Carrier proteins have specific binding sites for the substance and undergo conformational changes to facilitate its movement across the membrane (glucose transporters, ion channels)
• The rate of facilitated diffusion is saturable, as it depends on the availability of carrier proteins and their affinity for the substance
• Examples of substances that undergo facilitated diffusion include glucose, amino acids, and certain ions (potassium, chloride)

Active transport

• Active transport is the movement of substances across membranes against their concentration gradient, requiring the expenditure of energy (usually ATP)
• Primary active transport directly uses energy to move substances, while secondary active transport couples the movement of one substance to the concentration gradient of another (sodium-potassium pump, proton pumps)
• Active transport is mediated by specific carrier proteins or pumps that undergo conformational changes to translocate the substance across the membrane
• Examples of substances that undergo active transport include ions (calcium, sodium), neurotransmitters (dopamine, serotonin), and certain drugs (antibiotics, chemotherapeutics)

Endocytosis

• Endocytosis is the process by which cells engulf substances or particles by invaginating their plasma membrane to form vesicles
• Phagocytosis involves the uptake of large particles (bacteria, cell debris) by specialized cells (macrophages, neutrophils), while pinocytosis involves the uptake of fluids and solutes by most cell types
• Receptor-mediated endocytosis occurs when specific ligands bind to cell surface receptors, triggering the formation of clathrin-coated vesicles (low-density lipoprotein, transferrin)
• Substances internalized by endocytosis are typically degraded in lysosomes or transported to other cellular compartments for processing or storage

Absorption across barriers

• Absorption of substances occurs across various biological barriers that separate the external environment from the internal milieu of the body
• The structure and function of these barriers can significantly influence the absorption and distribution of toxicants

Gastrointestinal tract

• The gastrointestinal tract is a major site of absorption for ingested substances, with the small intestine being the primary region due to its large surface area (villi and microvilli)
• The absorption of substances across the intestinal epithelium can occur via passive diffusion (lipophilic compounds), facilitated diffusion (glucose, amino acids), or active transport (calcium, iron)
• Factors influencing gastrointestinal absorption include pH, food intake, gastrointestinal motility, and the presence of efflux transporters (P-glycoprotein)
• Substances absorbed from the gastrointestinal tract enter the hepatic portal system and undergo first-pass metabolism in the liver before reaching the systemic circulation

Respiratory tract

• The respiratory tract is a significant route of absorption for inhaled substances, particularly gases and small particles
• The alveoli in the lungs provide a large surface area for absorption, with the thin alveolar-capillary membrane allowing for rapid exchange of substances between the air and blood
• Factors influencing respiratory absorption include particle size, solubility, and the rate of ventilation
• Substances absorbed from the respiratory tract enter the pulmonary circulation and can be distributed throughout the body before undergoing metabolism

Skin

• The skin acts as a barrier to the absorption of substances, with the stratum corneum (outermost layer) being the primary barrier
• Lipophilic substances can penetrate the stratum corneum more readily than hydrophilic substances, which may require specific transport mechanisms or penetration enhancers
• Factors influencing dermal absorption include skin integrity, hydration, temperature, and the presence of hair follicles or sweat glands
• Substances absorbed through the skin enter the systemic circulation via the capillaries in the dermis and can be distributed throughout the body

Blood-brain barrier

• The blood-brain barrier (BBB) is a specialized barrier that regulates the exchange of substances between the blood and the central nervous system (CNS)
• The BBB is formed by tight junctions between endothelial cells of brain capillaries, astrocyte foot processes, and pericytes, which restrict the passage of many substances
• Lipophilic substances can cross the BBB more easily than hydrophilic substances, which may require specific transport systems (glucose transporter, amino acid transporters)
• Factors influencing BBB permeability include inflammation, age, and the presence of specific efflux transporters (P-glycoprotein, breast cancer resistance protein)

Bioavailability

• Bioavailability is a crucial concept in toxicology that describes the extent to which a substance enters the systemic circulation and becomes available for interaction with target sites
• Understanding bioavailability is essential for determining the potential toxicity of a substance and designing appropriate dosing regimens

Definition and importance

• Bioavailability is defined as the fraction of an administered dose that reaches the systemic circulation unchanged
• It is typically expressed as a percentage and can range from 0% (no absorption) to 100% (complete absorption)
• Bioavailability is important because it determines the amount of a substance that is available to exert its pharmacological or toxicological effects
• Factors that reduce bioavailability can lead to decreased efficacy or toxicity, while factors that increase bioavailability can lead to enhanced effects or adverse reactions

Factors influencing bioavailability

• Route of administration: Different routes of exposure (oral, inhalation, dermal, injection) can result in varying bioavailability due to differences in absorption and first-pass metabolism
• Physicochemical properties: Lipophilicity, molecular size, and solubility can influence the absorption and distribution of a substance, affecting its bioavailability
• Formulation: The formulation of a substance (tablet, capsule, solution) can impact its dissolution and absorption, leading to differences in bioavailability
• Food effects: The presence of food in the gastrointestinal tract can alter the absorption of substances by changing pH, motility, or interacting with the substance itself
• Metabolism: First-pass metabolism in the liver or gut wall can reduce the bioavailability of substances administered orally, as they are metabolized before reaching the systemic circulation
• Genetic factors: Variations in genes encoding enzymes involved in metabolism or transport can influence the bioavailability of substances

Methods for determining bioavailability

• In vivo studies: Bioavailability can be determined by measuring the concentration of a substance in blood or plasma over time after administration (pharmacokinetic studies)
• In vitro studies: In vitro dissolution tests can provide an estimate of bioavailability by measuring the rate and extent of substance release from a formulation
• Computational models: Physiologically based pharmacokinetic (PBPK) models can predict bioavailability based on the physicochemical properties of a substance and the physiological characteristics of the organism
• Bioequivalence studies: Comparative bioavailability studies can be used to demonstrate that two formulations of a substance (e.g., generic and brand-name drugs) are bioequivalent

Absorption vs distribution

• Absorption and distribution are two distinct processes that occur after a substance enters the body, and understanding their differences is crucial for predicting the fate and effects of toxicants

Key differences

• Absorption refers to the movement of a substance from the site of administration into the systemic circulation, while distribution refers to the movement of a substance from the blood to various tissues and organs
• Absorption is influenced by factors such as route of exposure, physicochemical properties, and biological barriers, while distribution is influenced by factors such as blood flow, tissue affinity, and protein binding
• The rate and extent of absorption determine the bioavailability of a substance, while the rate and extent of distribution determine its concentration in target tissues
• Absorption is typically a unidirectional process (from the external environment to the blood), while distribution can be bidirectional (from blood to tissues and vice versa)

Relationship between absorption and distribution

• The absorption of a substance is a prerequisite for its distribution, as the substance must first enter the systemic circulation before it can be distributed to various tissues
• The rate of absorption can influence the rate of distribution, as a rapidly absorbed substance will be distributed more quickly than a slowly absorbed substance
• The extent of absorption can influence the extent of distribution, as a higher bioavailable dose will result in higher concentrations of the substance in the blood and tissues
• Factors that affect absorption (e.g., route of exposure, formulation) can indirectly influence distribution by altering the amount of substance available for distribution

Absorption in toxicology

• Absorption is a critical process in toxicology, as it determines the amount of a toxicant that enters the body and becomes available for interaction with target sites
• Understanding absorption is essential for assessing the potential toxicity of substances and developing strategies for risk assessment and management

Relevance to toxicity assessment

• The rate and extent of absorption can influence the onset, duration, and severity of toxic effects, as well as the dose-response relationship
• Differences in absorption between species or individuals can lead to variations in susceptibility to toxicants and complicate extrapolation of animal data to humans
• Factors that enhance absorption (e.g., high lipophilicity, small molecular size) can increase the potential for toxicity, while factors that reduce absorption (e.g., poor solubility, efflux transporters) can decrease toxicity
• Knowledge of absorption mechanisms can help predict the potential for interactions between toxicants and other substances (e.g., food, drugs) that may alter absorption

Absorption of specific toxicants

• Metals: The absorption of metals (lead, cadmium, mercury) can occur through inhalation, ingestion, or dermal contact, with factors such as solubility, valence state, and particle size influencing absorption
• Pesticides: The absorption of pesticides can vary depending on the route of exposure and the formulation, with lipophilic pesticides (organochlorines) being more readily absorbed than hydrophilic ones (organophosphates)
• Solvents: Organic solvents (benzene, toluene) are typically well-absorbed through inhalation and dermal routes due to their lipophilicity and small molecular size
• Nanoparticles: The absorption of nanoparticles can be influenced by their size, shape, surface charge, and coating, with smaller particles generally having higher absorption rates than larger ones

Absorption in risk assessment

• Absorption data are used in risk assessment to estimate the internal dose of a toxicant that results from a given exposure scenario
• Physiologically based pharmacokinetic (PBPK) models incorporate absorption parameters to predict the concentration of a toxicant in target tissues over time
• Bioavailability data are used to adjust the external dose of a toxicant to the internal dose that is relevant for toxicity, allowing for more accurate risk characterization
• Absorption data can inform the selection of appropriate dose metrics (e.g., area under the curve, peak concentration) for use in dose-response assessment and derivation of toxicity reference values (e.g., reference doses, acceptable daily intakes)

Experimental methods

• Various experimental methods are used to study the absorption of substances in toxicology, ranging from in vitro assays to in vivo studies and computational models
• The choice of experimental method depends on the specific research question, the properties of the substance, and the available resources and expertise

In vitro absorption studies

• In vitro absorption studies use isolated cells, tissues, or artificial membranes to measure the permeability and transport of substances
• Cell-based assays (Caco-2, MDCK) can provide information on the absorption and metabolism of substances in the gastrointestinal tract or other barrier tissues
• Parallel artificial membrane permeability assay (PAMPA) uses an artificial lipid membrane to measure the passive permeability of substances
• In vitro dissolution tests can predict the bioavailability of substances by measuring their release from formulations under simulated physiological conditions
• Advantages of in vitro studies include high throughput, low cost, and reduced animal use, while limitations include the lack of complex physiological factors and potential differences between in vitro and in vivo conditions

In vivo absorption studies

• In vivo absorption studies involve the administration of a substance to a living organism and the measurement of its concentration in blood, tissues, or excreta over time
• Pharmacokinetic studies in animals (rodents, dogs, non-human primates) can provide information on the absorption, distribution, metabolism, and excretion (ADME) of substances
• Mass balance studies involve the administration of a radiolabeled substance and the measurement of radioactivity in excreta and tissues to determine the extent of absorption and distribution
• Bioavailability studies compare the systemic exposure (area under the curve, peak concentration) of a substance after different routes of administration or formulations
• Advantages of in vivo studies include the ability to capture complex physiological processes and the relevance to human exposure scenarios, while limitations include high cost, ethical concerns, and potential species differences

Computational models for absorption

• Computational models use mathematical equations and data from in vitro and in vivo studies to predict the absorption of substances
• Quantitative structure-activity relationship (QSAR) models relate the physicochemical properties of substances to their absorption, allowing for the prediction of absorption for untested compounds
• Physiologically based pharmacokinetic (PBPK) models incorporate anatomical and physiological parameters to simulate the absorption, distribution, metabolism, and excretion of substances in the body
• In silico models of gastrointestinal absorption (GastroPlus, SimCYP) can predict the oral bioavailability of substances based on their physicochemical properties and formulation characteristics
• Advantages of computational models include the ability to make predictions for a wide range of substances and exposure scenarios, reduced animal use, and the integration of data from multiple sources, while limitations include the need for high-quality input data and the potential for model uncertainty and variability.