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2. Toxicokinetics - the investigation of the time course of toxicant ingestion, circulation, digestion system, and excretionHow would we be able to foresee variability among individuals?How would we be able to extrapolate from creature models to people?. . . . . DosageExposure. ToxicEffects. PlasmaConc.. . . Site ofaction. Toxicokinetics.
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TOXICOKINETICS Wongwiwat Tassaneeyakul Department of Toxicology Khon Kaen University

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Toxicokinetics - the investigation of the time course of toxicant assimilation, circulation, digestion system, and discharge How would we be able to foresee inconstancy among people? How might we extrapolate from creature models to people? Site of activity Plasma Conc. Measurements Exposure Toxic Effects Toxicokinetics Toxicodynamics

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Toxicokinetic (TK) forms ABSORPTION DISTRIBUTION METABOLISM EXCRETION EXTERNAL BLOOD PLASMA PHASE-1 KIDNEYS MEMBRANE Oxidation LIVER BARRIERS xenobiotic lungs TISSUES salivation skin PHASE-2 pools sweat G.I. tract conjugation warehouses bosom drain lungs sinks

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Disposition of Xenobiotics ingestion dissemination discharge

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Structural model of cell layer The " lipid strainer\' demonstrate clarify how lipophilic little cpds can saturate through the film by latent dispersion hydrophilic cpds can\'t penetrate unless there is a particular layer transport channel or pump.

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Mechanism of Membrane Permeation Passive dispersion Active transport Facilitated transport Pinocytosis

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Transfer of Chemicals crosswise over Membranes Passive transport controlled by: - Permeability of surface -Concentration angle -Surface territory Permeability relies on upon: For cell layers: -Lipid dissolvability -pH of medium -pK of substance For endothelium size, shape and charge of concoction PASSAGE ACROSS MEMBRANES Active Passive Facilitated

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Uptake by Passive dissemination Uncharged particles may diffuse along conc. inclination until balance is achieved No substrate particular Small MW < 0.4 nm (e.g. CO, N 2 0, HCN) can travel through cell pores Lipophilic chemicals may diffuse through the lipid bilayer

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Uptake by Passive dissemination First request rate dispersion, relies on upon Concentration inclination Surface range (alveoli  25 x body surface) Thickness Lipid solvency & ionization Molecular size (film pore estimate = 4-40 A, permitting MW of 100-70,000 to go through)

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Weak Acids and Weak Bases HA <==> H + A - B + H + <==> BH + [ UI ] [ I ] [ UI ] [ I ] pKa = pH + log(HA/A - ) pKa = pH+ log(BH +/B) pKa = 4.5 (a frail corrosive) pH = 2 pH = 7.4 0.1 = [ I ] [ I ] = 9990 100 = [ UI ] [ UI ] = 100 100.1 = add up to medicate = 10090

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Flicks\' law and Diffusion dD/dt = KA (C o - C i )/t Where; dD/dt = rate of mass exchange over the layer K = steady (coefficient of penetrability) A = Cross sectional zone of film presented to the compound C 0 = Concentration of the toxicant outside the film C i = Concentration of the toxicant inside the layer t = Thickness of the film

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Facilitated Transport Carried by trans-layer transporter along focus angle Energy free May upgrade transport up to 50,000 folds Example: Calmodulin for encouraged transport of Ca ++

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Active Transport Independent of or against conc. angle Require vitality Substrate –specific Rate constrained by no. of bearers Example: P-glycoprotein pump for xenobiotics (e.g. OC) Ca-pump (Ca 2+ - ATPase)

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Uptake by Pinocytosis For vast atoms ( ca 1 um) Outside: in-collapsing of cell layer Inside: arrival of particles Example: Airborne toxicants crosswise over alveoli cells Carrageenan crosswise over digestive system

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Rate of Absorption The rate of ingestion decides the season of onset and the level of intense danger. This is to a great extent since time to top (Tmax) and most extreme fixation (Cmax) after every presentation rely on upon the rate of assimilation. Rate the accompanying procedures all together of quickest to slowest: INTRAVENOUS> INHALATION >ORAL > DERMAL EXPOSURE.

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Factors Affecting Absorption Determinants of Passive Transfer (lipid solvency, pH, pK, range, fixation inclination). Blood stream Dissolution in the fluid medium encompassing the engrossing surface.

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Factors Affecting GI Absorption Disintegration of measurements frame and disintegration of particles Chemical security of concoction in gastric and intestinal juices and proteins Rate of gastric purging Motility and blending in GI tract Presence and kind of sustenance

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Lungs Absorption For gasses, vapors and unpredictable fluids, pressurized canned products and particles all in all: huge surface range, thin boundary, high blood stream quick ingestion Blood:air segment coefficient – influence of respiratory rate and blood stream Blood:tissue segment coefficient

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Lungs Absorption REMOVAL OF PARTICLES Absorption of Aerosols and Particles : 1-Particle Size 2-Water dissolvability of the synthetic present in the vaporized or molecule Lymph Physical Phagocytosis

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Airway life structures bronchial tree trachea dispersion separate: ~20 mm add up to trade gas trade territory: ~80 m 2

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Airway life structures alveoli trachea vessels bronchial tree dissemination separate blood/air: ~20 mm add up to trade gas trade region: ~80 m 2

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Absorption Area in the Respiratory System Nasopharynge 5-30 µm Trachea Bronchi Bronchioles 1-5 µm Alveolar Region 1 µm

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Skin Absorption Must cross a few cell layers (stratum corneum, epidermis, dermis) to achieve veins. Variables critical here are: lipid solvency hydration of skin site (e.g. sole of feet versus scrotum)

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Other Routes of Exposure Intraperitoneal large surface range, vascularized, first pass impact. Intramuscular, subcutaneous, intradermal: retention through endothelial pores into the dissemination; blood stream is most imperative + different elements Intravenous

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Bioavailability Definition: the division of the controlled measurements achieving the systemic flow for i.v.: 100% for non i.v.: ranges from 0 to 100% e.g. lidocaine bioavailability 35% because of destruction in gastric corrosive and liver digestion system First Pass Effect

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Systemic flow Liver vein Liver supply route Vena portae and tributaries

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FIRST PASS EFFECT Intestinal versus gastric retention Wilkinson, NEJM 2005

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Extent of Absorption or Bioavailability Destroyed in gut Not assimilated Destroyed by gut divider Destroyed by liver Dose to systemic dissemination

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Bioavailability (F) Plasma fixation (AUC) o (AUC) iv i.v. course oral course Time (hours)

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Principle For xenobiotics taken by courses other than the iv, the degree of retention and the bioavailability must be comprehended keeping in mind the end goal to figure out if a specific introduction measurement will initiate dangerous impacts or not. It will likewise clarify why a similar dosage may bring about lethality by one course however not the other .

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Distribution is second period of TK process characterizes where in the body a xenobiotic will follow retention Perfusion-restricted tissue dispersion perfusion rate characterizes rate of blood stream to organs exceptionally perfused tissues (frequently more powerless) liver, kidneys, lung, cerebrum ineffectively perfused tissues (regularly less defenseless) skin, fat, connective tissues, bone, muscle (variable)

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Distribution into body compartments Plasma 3.5 liters . ( heparin, plasma expanders) Extracellular liquid 14 liters. (tubocurarine, charged polar mixes) Total body water 40 liters. (ethanol) Transcellular little. CSF, eye, hatchling (must pass tight intersections)

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Distribution Rapid process in respect to retention and elimination Extent relies on upon -blood flow -estimate, M.W. of molecule -lipid dissolvability and ionization -plasma protein binding -tissue official

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Distribution Initial and later stages: beginning dictated by blood stream later controlled by tissue fondness Examples of tissues that store chemicals: fat for exceptionally lipid solvent mixes bone for lead

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Alter plasma authoritative of chemicals 1000 atoms 90.0 99.9 % bound 1 100 particles free 100-overlay increment in free pharmacologically dynamic focus at site of activity. NON TOXIC

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volume of dissemination Chemicals seem to appropriate in the body as though it were a solitary compartment. The size of the compound\'s conveyance is given by the evident volume of circulation (Vd).

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Volume of Distribution (Vd) Volume into which a medication seems to circulate with a focus equivalent to its plasma fixation Amount of medication in body Vd = Concentration in Plasma

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Vd can be ascertained after an IV measurement of a substance that shows "one-compartment model" qualities. Vd = Dose/Initial Conc

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Drug L/Kg L/70 kg Sulfisoxazole 0.16 11.2 Phenytoin 0.63 44.1 Phenobarbital 0.55 38.5 Diazepam 2.4 168 Digoxin 7 490 Examples of evident Vd\'s for a few medications

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Competition-removal between xenobiotics low bioavailability high bioavailability tolbutamide + warfarin (antocoagulant) tolbutamide (hypoglycemic medication)

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Distribution Blood Brain Barrier – attributes: 1. No pores in endothelial film 2. Transporter in endothelial cells 3. Glial cells encompass endothelial cells 4. Less protein focus in interstitial liquid Passage crosswise over Placenta

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Free-plasma and erythrocyte-bound xenobiotics case: lead official to ALAD protein plasma Pb ++ Blood Pb ++ erythrocyte Pb ++

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CNS (mind) supple bone kidney bring down neurotoxicity higher renal lethality bring down plasma Pb ++ - higher erythrocyte Pb ++ lifted blood Pb ++ ALAD-2 polymorphism Free-plasma and erythrocyte-bound xenobiotics illustration: lead authoritative to ALAD protein CNS (cerebrum) light bone kidney higher neurotoxicity avg plasma Pb ++ avg erythrocyte Pb ++ normal blood Pb ++ ALAD-1 polymorphism .:tslides

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