Introduction to Toxicokinetics

Distribution Passage of drug molecules to liquid compartments and tissues in the body via transportation across the capillary membrane how much of body weight is water 50-70 percent what are the three major fluid compartments in the body extracellular intracellular transcellular Extracellular Includes blood plasma, interstitial fluid, and lymph Intercellular Fluid within all cells of the body Transcellular Includes cerebrospinal, (in and around brain and spinal cord,) intraocular fluid (within eyeballs) how many ways can drugs be distributed in the body 4 where can high molecular weight substances (such as evans blue dye) be distributed only in plasma small non ionized molecules like alcohol is distributed to ... all body fluids homogenously Most of the drugs are distributed in this explain the Non-homogenous (non-uni- pattern according to their abilities to pass form) distribution pattern through the cell membranes or affinities to the different tissues concentration in specific tissues Iodine in thyroid; chloroquine in liver; tetracyclines in bones and teeth; high lipophilic drugs in fat tissue uneven distribution of toxicants occurs due to physiochemical properties like pKa , lipid solubility, molecular weight, and protein/tissue binding 1/8 blood flow, barriers like placental and blood-brain, cell membranes and capillary walls Volume of Distribution relates to how does high molecular Weight affect leads to lower absorption and affects corabsorption rect dosage range Barrier, structural support, receptor sites, cell markers for recognition Cell Membrane Functions passive diffusion, filtration, facilitated difMembrane Permeability - mechanisms fusion, active transport, ion-pair, endocyof solute transport across membranes tosis Passive Diffusion requires Toxins dissolve and cross cell membranes following concentration gradient, lipid soluble, uncharged, low molecular weight Rate of diffusion influenced by the • Difference in concentration gradient • Surface area and thickness of cell membrane • Lipid solubility of the toxin • Ionisation state of toxin what do you have to take into consideration when dealing with passive diffusion of non- electrolytes lipid-water partition coefficient the ratio of the concentration of the drug What is the lipid-water partition coeffi- in a nonpolar liquid (representing memcient? brane) and an aqueous buffer (representing the plasma). Lipid-water partition coefficient (P) equa- P = [drug] in lipid phase/[drug] in aquetion ous phase if P is higher it means the drug is more soluble in lipid . if lower drug is more soluble in aqueous why is lipid solubility desirable lipophilic drugs are difficult to excrete The more C and H on the compound, the more lipid soluble the drug is and has a higher P The more O, S a compound has the more water soluble the compound is = lower P 2/8 what form does the drug have to be to pass through membrane via passive diffusion unionized / uncharged what is the problem with ionized forms of Ionized form is less lipid soluble and candrugs not easily cross body membranes how can you control the rate at which the drug/toxin is transferred by controlling the pH of the solution and/or the pKa of the drug/toxin, What is staurosporine? fungal toxin that induces apoptotic cell pathways and therapeutic agent that inhibits tumor cell growth by inducing cell death explain Filtration Passage of molecules through membrane pores, transports polar and slightly larger molecules what does filtration require • Concentration gradient • Transmembrane protein / specific protein how does size affect filtration rate • Smaller compound - transfer rapidly • Larger compound - retained Intermediate compound - barrier where does filtration occur pores or through the spaces between cells: • Capillary endothelial membranes • Renal glomerulus Facilitated diffusion • Carrier or receptor-mediated • Selective to specific molecules e.g. glucose • It can be saturated • Does not require ATP • Does not go against the concentration gradient • Bi-directional - no drug accumulation • Requires specific carrier protein Active Transport Goes against concentration gradient, requires ATP, mediated by carrier proteins, selective, one-way process • Polar molecules • Large molecules 3/8 what kind of molecules does active transport transfer Endocytosis Ingestion of large particles or uptake of fluids in vesicles, requires ATP, includes phagocytosis and pinocytosis endocytosis steps 1. folds inward forming cavity 2. molecules trapped within cavity as enclosed membrane forms around them (vesicle) 3.vesicle detached from membrane and processed by cell Cyanide Released from natural substances, enters cells by passive diffusion or facilitated transport, inhibits cellular respiration Paraquat Herbicide toxic to lungs, accumulates via active transport in specific cells, leading to pulmonary damage Phagocytosis Type of endocytosis involving engulfing large particles. detection , attachment , ingestion , fusion , elimination attachment : The phagocyte makes contact and attaches to the target cell. This initiates the formation of pseudopodia, an extension of the cell membrane that helps to surround the target. ingestion The surrounded target cell gets enclosed within a vesicle when the membrane of pseudopodia fuses. called a phagosome fusion The phagosome then gets fused with the hydrolytic enzymes of the lysosome, to form a structure called phagolysosome. Lysosomes thus help to digest the materials contained within the vesicle elimination : This is the final step during which the digested foreign particle gets expelled from the cell. 4/8 Pinocytosis Endocytosis process for absorbing fluids and nutrients (cell- drinking ) Receptor-mediated endocytosis (RME) Selective uptake process using membrane receptor proteins Caveolae Cell membrane pits for specific molecule uptake where are caveolae found smooth muscles, adipocytes, fibroblasts, and endothelial cells what cholesterol-binding protein takes up molecules caveolin Ion-pair transport Transport method for ionized toxins or drugs • Absorbed after complexing with oppositely charged ions are absorbed. when is ion pair transport used when toxins or drugs that ionise at all pH conditions Carrier Highly ionized compound aiding drug transport unbound drug in the plasma is ... pharmacologically active Protein / Tissue Binding Process where drugs bind to plasma proteins or tissues may prolong their action what is albumin • The primary serum protein responsible for drug binding • The strongest affinity for weak acid and hydrophobic drugs • 1 or 2 selective high affinity binding sites for week acidic drugs • Saturable • One plasma protein can bind a limited number of drug molecule Non-selective • More than one kind of drug which has different chemical strucProperties of plasma protein-drug bindtures or pharmacological effects can be ing: bound to the space on plasma protein • Reversible • The bonds between the drug and plasma protein are weak bonds like hydrogen or ionic bonds 5/8 drugs which are highly bound (>90%) with small volume of distribution changes in protein binding affect bound drug is inactive whilst bound and synthetic distribution and glomerular filthis limits tration Storage Depots Specific body tissues where drugs may accumulate what drugs accumulate in bone Ca2+ binding drugs accumulate here (ex tetracycline ) what drugs accumulate in fat lipophilic drugs accumulate here and are released slowly (ex thiopental) what drugs accumulate in liver many drugs accumulate in the liver due to an affinity for hepatic cells (antimalaria agent - quinacrine ) Redistribution Gradual return of drugs from tissues to plasma to form equilibrium Blood Perfusion Transfer of drugs from circulation to tissues based on blood flow what organs have high perfusion rate (ml/100g tissue/min) Kidney, liver, brain and heart low perfusion rate Skin, resting skeletal muscle and bone Capillary Tiny blood vessels transporting blood and nutrients Continuous Capillaries Common type of capillary with closely spaced endothelial cells what drugs pass through capillary pores drugs that do not bind to plasma proteins lining that contains pores (also called intracellular clefts) that let only small molContinuous nonfenestrated capillaries ecules pass through. These molecules include water, glucose, hormones and gases. where do they exist This type of capillary exists in your nervous system, skin and lungs. 6/8 Continuous fenestrated capillaries larger openings (fenestrations) between the cells that allow the quick exchange of substances. These substances include nutrients and blood. where are they found kidneys, small intestine and endocrine glands. sinusoidal capillaries discontinuous. These capillaries have even larger gaps and pores. Sinusoidal where can you find them in your liver, spleen, lymph nodes, bone marrow and endocrine glands Blood-Brain Barrier Selective barrier limiting substances from entering the CNS what molecules can pass through bbb Non-ionized, highly lipophilic, small molecules can pass into the CNS what antibiotic can pass through bbb when inflamed but not when healthy penicillin type of junction in BBB Tight junctions between capillary endothelial cells Endothelium of the capillary wall • Thick basal lamina surrounding the capSubstances in the brains capillaries must illaries pass • Astrocyte 'feet' that give the signals to create tight junctions when does the BBB mature after about 4 months Placental Barrier Barrier regulating drug passage to the fetus Fat-soluble substances (including all what substance can diffuse through plapsychoactive drugs)diffuse rapidly and cental barrier without limitation volume of distribution vod = total amount of drug in body (mg) (dose) / plasma conc (mg/L) The greater the volume of distribution of a drug, the more... likely it is to get into the tissues 7/8 what does vod help us calculate • The amount of drug found in the body at a particular time from the analyzed plasma drug concentration. • The drug dose (loading dose) that has to be given (required) to obtain a desired plasma drug concentration clincal predictions for vod • If Vd = 3L, you can assume drug/toxin is distributed in plasma only • If Vd = 18L, you can assume drug/toxin is distributed in plasma and tissues • If Vd > 46L, the drug/toxin is likely stored in a depot because the body only contains 40-46L of fluid Loading dose (mg) = [Cp (mg/L) x Vd (L)] /F loading dose calculation • Cp represents the desired plasma concentration of drug • Vd represents the volume of distribution • F represents the bioavailability of drug (IV administration = 1) 8/8