Body Distribution and Toxicokinetics PDF

16-02-2022 1 Body Distribution andToxicokinetics Casaretts & Doull Toxicology Chapter 5 and 7...

16-02-2022 1 Body Distribution andToxicokinetics Casaretts & Doull Toxicology Chapter 5 and 7 Prof.dr. Martin van den Berg Utrecht University, Utrecht, The Netherlands ([email protected]) 1 DISPOSITION OF CHEMICAL Equals composite actions of absorption, distribution, 2 biotransformation, and elimination. Main barriers separate higher organisms from environment: skin, lungs, and gastrointestinal tract Black lines = major pathways of absorption, Blue lines = distribution Green lines = elimination Enterohepatic circulation = red. 2 1  16-02-2022 TARGET TISSUE OR CELLS Fundamental concept =the “dose makes the poison.” 3 A chemical is absorbed into the bloodstream or lymphatics and distributed throughout the body The site where it produces damage is called target organ or tissue One compound can have several target organs Several chemicals may have same target organ Poor absorption will limit or prevent toxicity A chemical well absorbed but rapidly biotransformed or eliminated is less likely to be toxic 3 CHEMICALS PASS THROUGH CELL MEMBRANE 4 Epithelium of the skin, cell layers of the lungs or gastrointestinal (GI) tract, capillary endothelium, and ultimately cells of target organ/cells All plasma membranes remarkably similar. Basic composition of cell membrane is lipid bilayer (primarily phospholipids, glycolipids, and cholesterol). In membranes, polar head groups oriented toward outer and inner surfaces Hydrophobic tails oriented inward form a continuous hydrophobic inner space 4 2  16-02-2022 PASSIVE TRANSPORT 5 Simple Diffusion Compounds cross membranes by simple diffusion moving from regions of higher concentration to regions of lower concentration Smaller hydrophilic molecules is, passes membranes more readily by simple diffusion through aqueous pores E.g., a water-soluble compound such as ethanol is rapidly absorbed into the blood from the GI tract and is just as rapidly distributed throughout the body by simple diffusion from blood into all tissues. For larger organic molecules with differing degrees of lipid solubility, the rate of transfer across membranes correlates with lipophilicity 5 ROLE OF PH IN TRANSPORT AND UPTAKE 6 Ionized chemicals usually have low lipid solubility and not permeate readily through the lipid domain of a membrane Some transfer organic anions and cations (depending on their molecular weight) through the aqueous pores, but a slow and inefficient process Nonionized forms of weak organic acids and bases are more lipid soluble and can diffusion across the lipid domain of membrane Transport rate of the nonionized forms proportional to its lipid solubility Gastric juice is acidic (pH ≈ 2) and intestines are nearly neutral (pH ≈ 7), Uptake due the lipid solubility of weak organic acids or bases can differ significantly in two areas of gastrointestinal tract 6 3  16-02-2022 ABSORPTION BY THE GASTROINTESTINAL TRACT 7 Many environmental chemicals enter the food chain and are absorbed together with food from the GI tract Accidental ingestion is most common route of unintentional exposure (especially for children) and intentional overdoses View GI tract as a tube traversing the body and its contents remain outside of the body Absorption of toxicants can take place along the entire GI tract, even in the mouth and the rectum 7 ROLE OF PH GI TRACT AND DRUG ABSORPTION 8 Acetaminophen Salicylic acid (aspirin) 8 4  16-02-2022 SPECIAL TRANSPORT ACROSS MEMBRANES GI TRACT For many compounds movement across membranes cannot be 9 explained by simple diffusion or filtration. Distribution of Specialized Transport Systems in the Small Intestine of Man and Animals 9 10 Question: Which of the following statements is TRUE a) The pH value of the gastrointestinal tract determines in which part a chemical is take up b) The lower part of the GI tract e.g. colon is very acidic c) Ionized molecules are slower absorbed from the GI than neutral molecules d) The pH of the stomach causes more ionization of acid pharmaceutical www.wooclap.com/CDKINETICS 10 5  16-02-2022 ACTIVE TRANSPORT IN ABSORPTION 11 Active transport is characterized by (1) Movement of chemicals against electrochemical or concentration gradients (2) Saturability at high substrate concentrations, (3) Selectivity for certain structural features of chemicals (4) Competitive inhibition by chemical congeners or compounds that are carried by the same transporter (5) Requirement for expenditure of energy, so that metabolic inhibitors block the transport process. Transporters mediate the influx (uptake) or efflux of xenobiotics Divided into two categories; either active or facilitated transfer of compounds. Major ABC (ATP Binding Cassette)Transporters ABC transporters exhibit characteristics active Involved in Xenobiotic Disposition transport and require expenditure of energy to function. 11 ROLE OF TRANSPORT PROTEINS IN ABSORPTION 12 Many xenobiotic transporters expressed in GI tract, where they mediate increase or decrease absorption Efflux transporters particularly relevant to the disposition of compounds, because of their reductive role in the absorption and detoxification processes Xenobiotic transport systems present in the human gastrointestinal tract 12 6  16-02-2022 Number of toxicants actively absorbed by the GI tract is low most enter body by simple diffusion 13 Lipid-soluble substances absorbed by diffusion more rapid and extensive than water-soluble substances Extremely lipid-soluble chemicals are unlikely to dissolve in the aqueous fluids within the GI tract limiting absorption Water-soluble substances may be absorbed to some degree. E.g., oral absorption is about 10% of lead, 4% of manganese, 1.5% of cadmium, and 1% of chromium salts Particles and particulate matter also absorbed by GI tract. Particle size major determinant of absorption (lipid solubility or ionization less important) Particles size inversely related to absorption. E,g., metallic mercury relatively nontoxic, powdered arsenic more toxic than granular form 13 Question: 14 Chromate salts can be divided in soluble (Na2CrO4) and non-soluble (PbCrO4) compounds Which of the following statements is true? a) Absorption is lower for non soluble chromate salts b) The levels of chromate ion (CrO42-) in blood will be higher for soluble salts c) Absorption for Na2CrO4 and PbCrO4 will be similar from the GI tract d) PbCrO4 maybe more toxic than Na2CrO4 after ingestion www.wooclap.com/CDKINETICS 14 7  16-02-2022 NANOPARTICLES 15 Increasing interest (nano/micro)particles of very small diameter used in a variety of chemical and biological processes. Nanoparticles or nanomaterials typically less than 100 nm in size and toxicity mostly unknown, Greater absorption smaller (50 nm) particles compared to larger (100 nm) particles, 300-nm particles minimally absorbed. Multistep process required to translocate through intestinal barrier. Surface characteristics contribute to absorption (hydrophobic, nonionized particles more extensive absorption than those with ionized surface) Gut-associated lymphoid tissue predominant absorption pathway GI tract Donahue, Advanced Drug Delivery Reviews, 2019 15 SPECIES DIFFERENCES IN ABSORPTION 16 Species differences in absorption across the GI tract are widely recognized The factors contributing to species differences in absorption are not fully understood Anatomical and physiological aspects likely contribute species Significant species differences in the pH along the GI tract exist Nadolol = medication High Blood Pressure, Cardiac problems Absorption & Excretion in Rats, Dogs, and Humans After Nadolol Dosages* 16 8  16-02-2022 IMPORTANT ABSORPTION PROCESSES IN THE GUT 17 Processes of importance in rate and extent of absorption and bioavailability from the GI tract after oral administration of solid dosage forms CM = carrier-mediated absorption; Passive = passive absorption; EG = intestinal extraction; EH = hepatic extraction; Fa = fraction absorbed; F = bioavailability. Lennernäs et al. Journal of Pharmaceutical Sciences, Vol. 104, 2702–2726 (2015) 17 18 Question 1) Which of the following might increase the toxicity of a toxicants administered orally? a. increased activity of the MDR transporter (p-glycoprotein). b. increased biotransformation of the toxicant by gastrointestinal cells. c. increased excretion of the toxin by the liver into bile. d. increased dilution of the toxin dose. e. increased intestinal motility. www.wooclap.com/CDKINETICS 18 9  16-02-2022 ABSORPTION BY THE LUNGS Gases and Vapors 19 Vapor is gas form of substance that also exist as liquid or solid. Most organic solvents evaporate and produce vapors, Some solids also sublimate into a gaseous form. Absorption gases in lungs differs from intestinal and skin absorption that dissociation of acids/bases and lipid solubility less important Diffusion through lung cell membranes is not rate-limiting At least three reasons: 1) Ionized molecules have very low volatility. 2) Pneumocytes (epithelial cells lining alveoli) are very thin and capillaries in close contact with the pneumocytes making distance to diffuse very short. Third, 3) Chemicals absorbed by lungs removed rapidly by blood that moves rapidly through extensive capillary lung network 19 AEROSOLS AND PARTICLES IN THE LUNG 20 Important characteristics affecting absorption aerosols are size and water solubility Particulate matter (diameters ≈ 2.5 μm “fine particles”) are deposited mainly in tracheobronchiolar regions May be cleared by retrograde movement of the mucus layer in the respiratory tract Particles ≈ 1 μm and smaller penetrate alveolar sacs of the lungs Ultrafine particles or nanoparticles (10 to 20 nm) have greatest likelihood of depositing in alveolar region. These extremely small particles may be absorbed into blood or cleared through lymphatics after scavenged by alveolar macrophages Particle distribution in the lungs relative to size. Overall removal particles from alveoli relatively inefficient 20 10  16-02-2022 REMOVAL OR ABSORPTION OF PARTICULATE MATTER FROM ALVEOLI 21 Three major mechanisms: 1) Particles deposited on fluid layer alveoli aspirated (↑↑) onto mucociliary escalator of the tracheobronchial region. 2) particles from alveoli may be removed by phagocytosis. (alveolar macrophages). 3) Removal via the lymphatics via endothelial cells lining lymphatic capillaries M, Klinger-Strobel (2015). Aspects of pulmonary drug delivery strategies for infections in cystic fibrosis - where do we stand?. Expert Opinion on Drug Delivery. 21 ABSORPTION THROUGH THE SKIN 22 Skin largest body organ providing good barrier separating organisms from their environment In general, human skin into contact with many toxic chemicals, but absorption limited by relatively impermeable nature The skin comprises two major layers; epidermis and dermis Epidermis is outermost layer and contains keratinocytes that metabolically competent and able to divide The stratum corneum represents most important barrier to preventing fluid loss from the body and prevent the absorption of xenobiotics Absorbed chemical must pass barrier of the stratum corneum and then other six layers of the skin 22 11  16-02-2022 ABSORPTION THROUGH THE SKIN 23 All toxicants move across the stratum corneum by passive diffusion. Lipophilic (fat-soluble) compounds are absorbed more readily Penetration of hydrophilic (water-soluble) compounds more limited. Nonpolar toxicants diffuse proportional to lipid solubility and inversely related to molecular weight Lipophilic compounds passage through dermis may be rate-limiting. Hydrophilic compounds more likely penetrate skin through appendages e.g., hair follicles Factors that influence absorption through skin, include (1) the integrity of the stratum corneum, (2) the hydration state of the stratum corneum, (3) temperature, (4) solvents as carriers, (5) molecular size (> 400 Da poor dermal penetration) Nanoparticles may exhibit dermal absorption but overall absorption is relatively low For nanomaterials, hair follicles can contribute to dermal penetration, 23 SPECIES DIFFERENCES IN DERMAL ABSORPTION 24 Composition and thickness of stratum corneum highly variable across species. Stratum corneum much thicker in humans than in most animals, making human skin less permeable. Thinner stratum corneum in animals often compensated by hair cover, diminishing direct contact. Sweat and pilosebaceous ducts vary across species Important rate-limiting step in absorption is cutaneous blood flow. Skin plays important thermoregulatory function in humans as opposed to furred animals. 24 12  16-02-2022 BODY DISTRIBUTION 25 After entry into bloodstream toxicant distributes to tissues throughout the body distribution to tissues determined primarily by blood flow and diffusion out of the capillary bed into the cells Final distribution depends on affinity chemical for various tissues. Initial phase of distribution dominated by blood flow Final distribution in organs determined largely by (bio)chemical properties Penetration of into cells by passive diffusion or special transport processes Small water-soluble molecules and ions diffuse through aqueous channels or pores in cell membrane Lipid-soluble molecules readily permeate the membrane itself 25 VOLUME OF DISTRIBUTION 26 A key concept in understanding the disposition of a toxicant is volume of distribution (Vd) Primary determinant of concentration in blood used to quantify distribution throughout the body Defined as volume in which chemical need to be uniformly dissolved to produce observed blood concentration 26 13  16-02-2022 PLASMA PROTEINS AS STORAGE DEPOT 27 Binding to plasma proteins is major storage depot Several different plasma proteins bind xenobiotics and some endogenous constituents of the body. Albumin is major protein in plasma binding many xenobiotics Albumin, most abundant protein in plasma and serves as depot and multivalent transport protein for many endogenous and exogenous compounds. Protein–ligand interactions occur primarily as a result of hydrophobic forces, hydrogen bonding, and Van der Waals forces. Because of high molecular weight, plasma proteins and bound toxicants cannot cross capillary walls. 27 BINDING PLASMA PROTEINS AND TOXICITY 28 Binding of chemicals to plasma proteins is important concept in toxicology 1. Toxicity typically manifested by amount of unbound (free) chemical entering cell 2. Species differences in plasma protein binding influencing disposition of xenobiotics Species specific binding to plasma proteins can influence half- life xenobiotic in species (besides role metabolism!) 28 14  16-02-2022 MAJOR STORAGE DEPOTS IN BODY 29 Liver and Kidney High capacity as a storage depot for many chemicals. Both concentrate more toxicants than usually all other organs combined Active transport or binding to tissue components often involved Fat Many stable and lipophilic organic compounds accumulate in fat (food chain) Lipophilicity of these compounds permits rapid penetration of cell membranes lipophilic toxicants are often concentrated in body fat and retained for a very long time (humans vs rodents!) Bone Compounds e.g. fluoride, lead, and strontium incorporated and stored in the bone matrix. E.g., 90% of lead in the body is found in the skeleton 29 MEMBRANES PROTECTING THE BRAIN 30 Access toxicants to brain restricted by two barriers: Blood–brain barrier (BBB) and Blood–Cerebral Spinal Fluid Barrier (BCSFB) Neither is absolute barrier to passage of toxicants into the CNS, but many chemicals do not enter brain in appreciable quantities (e.g., problems brain tumors and chemotherapy) Several transport proteins play significant role in limiting uptake toxicants in the brain 30 15  16-02-2022 PLACENTA PROTECTING THE UNBORN CHILD Placental barrier associated has main function, but not 31 exclusively, to protect the fetus against noxious substances or toxicants present in blood from the mother. Placenta also multifunctional organ providing: 1. nutrition for the unborn, 2. exchanges maternal and fetal blood gases, 3. disposes fetal excretory material, 4. maintains pregnancy through hormonal regulation Placental structure and function show more species differences than any other mammalian organ (Animal experiments) Many toxicants cross placenta and same factors that determining passage of xenobiotics across biological membranes are important for placental transfer, including: 1. degree of ionization, 2. lipophilicity, 3. protein binding 4. molecular weight 5. blood flow 6. concentration gradient across the barrier Transport systems contributing to the barrier function human placenta Wikipedia 31 URINARY EXCRETION Kidney very efficient organ for elimination toxicants 32 Functional is nephron, comprising: 1. Glomerulus 2. Capillary tuft for filtration of blood, and 3. Cubule elements produce and concentrate urine Toxic compounds are excreted in urine Excretion of small molecular weight (> kp lower left panel) Elimination of metabolite much slower than its formation (km