TOXICOKINETICS Wongwiwat Tassaneeyakul Department of Toxicology Khon Kaen UniversitySlide 2
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 ToxicodynamicsSlide 3
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 sinksSlide 4
Disposition of Xenobiotics ingestion dissemination dischargeSlide 5
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.Slide 7
Mechanism of Membrane Permeation Passive dispersion Active transport Facilitated transport PinocytosisSlide 8
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 FacilitatedSlide 9
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 bilayerSlide 10
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)Slide 11
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 = 10090Slide 12
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 filmSlide 13
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 ++Slide 14
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)Slide 15
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 systemSlide 16
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.Slide 17
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.Slide 18
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 sustenanceSlide 19
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 coefficientSlide 20
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 PhagocytosisSlide 21
Airway life structures bronchial tree trachea dispersion separate: ~20 mm add up to trade gas trade territory: ~80 m 2Slide 22
Airway life structures alveoli trachea vessels bronchial tree dissemination separate blood/air: ~20 mm add up to trade gas trade region: ~80 m 2Slide 23
Absorption Area in the Respiratory System Nasopharynge 5-30 µm Trachea Bronchi Bronchioles 1-5 µm Alveolar Region 1 µmSlide 24
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)Slide 25
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 IntravenousSlide 26
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 EffectSlide 27
Systemic flow Liver vein Liver supply route Vena portae and tributariesSlide 28
FIRST PASS EFFECT Intestinal versus gastric retention Wilkinson, NEJM 2005Slide 29
Extent of Absorption or Bioavailability Destroyed in gut Not assimilated Destroyed by gut divider Destroyed by liver Dose to systemic disseminationSlide 30
Bioavailability (F) Plasma fixation (AUC) o (AUC) iv i.v. course oral course Time (hours)Slide 31
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 .Slide 32
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)Slide 33
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)Slide 34
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 officialSlide 35
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 leadSlide 36
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 TOXICSlide 37
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).Slide 38
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 PlasmaSlide 40
Vd can be ascertained after an IV measurement of a substance that shows "one-compartment model" qualities. Vd = Dose/Initial ConcSlide 41
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 medicationsSlide 42
Competition-removal between xenobiotics low bioavailability high bioavailability tolbutamide + warfarin (antocoagulant) tolbutamide (hypoglycemic medication)Slide 43
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 PlacentaSlide 44
Free-plasma and erythrocyte-bound xenobiotics case: lead official to ALAD protein plasma Pb ++ Blood Pb ++ erythrocyte Pb ++Slide 45
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
I.P.I.A. “E.Majorana” – Messina. PROGETTAZIONE MODULARE FINALIZZATA ALL’ACQUISIZIONE ...
OFFERTE PUBBLICHE DI ACQUISTO O DI SCAMBIO. Definizione (Art. 1, com. 1 – lett. v) TUF).
www.agenziaentrate.it. Registrazione Telematica Contratti di locazione. Contratti di Locazi ...
Fatiga. Debemos evitar el cansancio ocasionado por la labor desempeñada que impide al trabaj ...
Employment Ventures www.employmentventures.org Kim Coleman Chief Executive Officer ceo@emp ...
Introduction. A framework of the Software Requirements for Crop management based on SRS Cond ...
GRUPA KAP I TAŁOWA. Kielce 2010. Kolporter. Trochę historii. 2 maja 1990 początek dzi ...
ADSR Systems - the Reactor. Tony Roulstone 13 April 2010. Contents. Challenge of the ADSR ...
Hexavalent Chromium Cr (VI). National Emphasis Program. New OSHA Instruction . National Emp ...
Causas de Incendios y Explosiones. Electricidad. Fumado. Incendiarismo. Materiales Sobreca ...
Choosing the Right Telescope. Discussion guided by: Thomas C. Smith, Director of the Dark R ...
Stephens College Alumnae Association Board. Effective after Reunion 2007.
Emma Willard (1787-1870). Fall 2006 EDCI658. Who Is Emma Willard?. Born on February 23, 17 ...
FITODEPURACIÓN. Arzate Garduño Cristina Contreras Núñez Erika Domínguez Pérez Mayra ...