Toxicokinetics = Toxicokinetics is the study of the drug movement around the body (Absorption, Distribution, metabolism, and Elimination) = Toxicokinetic data is best derived using radio labeled dose of the drug. This allows for following the fate of the drug, metabolic products, distribution in the tissue, stor See CON ET LERo Irae teeth (Oo Unfortunately, these methods do not JK A rele knowledge about proportion of the drug left intact to its metabolites. = TK is concerned with what the body does to the toxicant.TOXICOKINETICS Ingestion Inhalation ‘Skin penetration Non-compartment Parser Absorption 722 onder ofteacton Fist Quantitative model Circulation Compartment ri gr [Adipose fssue Physiological based TK Distribution. /-Fichy persed cgen Blood-brain barrier Toxicokinetics | Phase 4 )_ Metabolism CPrase 2 Kidney. Lung Feces Saliva Lactation Sweating ExcretionToxicodynamics = Toxicodynamics is the study of toxic actions of xenobiotic substances on living systems. = Toxicodynamics is concerned with processes and changes that occur to the drug at the target tissue, including metabolism and binding that results in an adverse effect. = Simply, TD is concerned with what the toxicant do to the bodySite of action == Toxicokinetics ToxicodynamicsCfontconneneS> TOXICODYNAMICS ADMINISTERED DOSE COMPOUND AT SITE OF ACTION ADVERSE OR TOXIC EFFECT ABSORPTION DISTRIBUTION METABOLISM EXCRETION PROTEIN BINDING CELLULAR CHANGESToxicokinetic (TK) processes ABSORPTION EXTERNAL MEMBRANE BARRIERS xenobiotic } skin G.L tract lungs DISTRIBUTION BLOOD PLASMA +f TISSUES depots METABOLISM EXCRETION PHASE-1 KIDNEYS: LIVER lungs saliva sweat breast milkDisposition of Xenobiotics Ingestion Inhalation Gastrointestinal tract Intravenous 4 Blood and lymph Intraperitoneal Subcutaneous Intramusculer Dermal extracellular Et fui ‘Secretory Structures Son tissue | bone“¢ ad lipid bilayer a transf yey esti , eee Yue Kom EU ESTE transport proteinToxicokinetics (ADME) = Toxicokinetics study four processes: Tera Ueroy gob Coye) 2, Distribution 3. Metabolism 4, Excretion Metabolism and excretion processes are combined as a single process called eliminationThe toxicokinetics of a chemical are determined by measuring the concentrations of the chemical in plasma (usually) or blood at various times following a single dose. The fundamental parameters that define the rates and extents of distribution and elimination are derived from data following an intravenous or oral dose.b. Oral administration-rapid absorptionImportant principles of toxicokinetics = The effect which a drug produces is dependent on: 1. The dose 2, The concentration in the target organ. = The kinetics of a drug may differ from therapeutic dose to its toxic dose = Toxicokinetics is important in predicting the FEI Mece ec eleTiCO eye Moraer esToxicokinetics and toxicity Toxicity depends on: PRUE Emenee eA La teat ce enema = The rate and amount (extent) of drug absorbed; toxicity will be low at slow absorption rates. This means that a highly toxic drug that is poorly absorbed may have same hazard as another with low toxicity but is highly absorbed. = The distribution of drug within the body; where most drugs are distributed in highly perfused organs like brain, liver and kidneys. However, in some cases, the organ in which the drug Reo reore ebb mi ceottel WeSC mU UAC ETN eayaUNT example is organochlorine compounds concentrated in adipose tissue while the target organ is the brain.The efficiency of biotransformation and nature of metabolites; where, in some cases, a drug may be transformed to a more toxic metabolite or a more lipid soluble or water soluble metabolite, which affects absorption and distribution CU iam MeO EEK mel membranes and interact with cell constituents. Example, some organochlorines affect the DNA The amount and storage duration of the drug or its metabolites in the tissue. These may induce toxicity after a long time after exposure. Lead in bones is an example The rate and site of excretion; where the more rapid the excretion, the less toxicity it will produce1. Absorption The term absorption describes the process of the transfer of the parent chemical from the site of administration into the general circulation, and applies whenever the chemical is administered via an extravascular route (i.e. not by direct intravascular stiifaes (On) s Many chemicals will be metabolized or transformed during their passage from the site of administration into the general circulation, so that little parent chemical may ee ier Relea E LL Be Semi Cpe TNO m confusion in discussing the ‘extent of absorption’ depending on whether the data refer to the parent chemical, or to metabolites or both (when radiolabeling is used). This confusion is ee Mot MIRO MIRO MMMM NUE NED ELIT nM Gitte fraction of the dose administered that reaches the general circulation as the parent compound) to describe the extent of absorption.oS Oo Mechanism of Membrane Permeation Pa eISSN TEU) 8) . Active transport . Facilitated transport . Pinocytosis and phagocytosisa Drugs are absorbed by the following processes: 4 . Passive transport This can occur by simple diffusion due to concentration elton mom By passage of drugs through the pores (of the kidney and capillaries), i.e. by filtration Passive transport is affected by: Ability of the drug to dissolve in the lipid portion of the cell prtouildettc DURST Mia lateem eT SRLS ase (Hed omate Oty ete Tel Tat Ory SIE Tomcat ey me KOO PANO ele to pass Dero e ROMINA e UB EBON NCAZen CoetelUptake by Passive diffusion e Uncharged molecules may diffuse along conc. gradient until equilibrium is reached e No substrate specificity ¢ Small MW < 0.4 nm (e.g. CO, N,0, HCN) can move through cell pores ¢ Lipophilic chemicals may diffuse through the lipid bilayerUptake by Passive diffusion First order rate diffusion, depends on Concentration gradient Surface area (alveoli > 25 x body surface) Thickness Lipid solubility & ionization Molecular size (membrane pore size = 4-40 A, allowing MW of 100-70,000 to pass through)Flicks’s law and Diffusion dD/dt = KA(C,-C,)/t A aTeik dD/dt = rate of mass transfer across the membrane K = constant (coefficient of permeability) A = Cross sectional area of membrane exposed to the compound Co = Concentration of the toxicant outside the membrane G = Concentration of the toxicant inside the membrane ia = Thickness of the membrane2. Special transport Two types of special transport mechanisms can be identified: 1 Active diffusion: = Independent of or against conc. gradient = Require energy = Substrate —specific = Rate limited by no. of carriers = Example: Ca-pump (Ca?* -ATPase)2. Facilitated diffusion: Occurs when a drug has a specific carrier protein, and does not occur against concentration gradient = Carried by trans-membrane carrier along concentration gradient = Energy independent = May enhance transport up to 50,000 folds = Example: Calmodulin for facilitated transport of Ca?*3. Additional transport: occurs by endocytosis; where : = Phagocytes (cell eating) engulf the solid large particles suspended in the intracellular fluid = Pinocytes (cell drinking) in which very small suspended particles or liquids are engulfedFactors affecting gastrointestinal absorption 1. Types of cells at the specific site: An example is the subli cells which are highly vascularized which allows for rapid absorption 2. Period of time that drugs remain at the site: Drugs are poorly absorbed within the mouth because the Potente Mehatteg Soro nee Meee RLS wes OCIS high absorption can occur in the intestine due to the long time a drug spends therenn Repose This factor affects the 1onizability of the drug. The acidic nature of the fluid in the stomach facilitates the absorption of weakly acidic drugs, while both weakly acidic and basic drugs are well absorbed in the small intestine since the pH there is almost neutral 4. The concentration at the absorption site 5. Presence of food or binding substances: SUTRA Melons Nomi euo eo lie-lbloeo mislm ines drug and thus will lower its absorption6. Rate of gastric emptying: UNTO nplrpecom Keone Melee g nen ETM IITs romero ella Kersey OAREE Treo ilcoseiee enol eLn ya This will decrease the amount absorbed in the stomach SS Zatiemnitesrec- teat te- Tarun er-leseyuoree mmm Lease ele 8. Absorbing surface area of the intestine 9. Blood flow to the site 10. Intestinal bacteria and gastrointestinal enzyme level 11, General condition of the patient: (oie oem rece emi EIN MIU E-veCcostrewlso yee (One IPAS Pyare a oer E LO MAAN Hom ERS Wen (eno m Ooi w touta Factors affecting pulmonary absorption 1. Solubility of the drug in the blood 2. Particle size Large particles are deposited in the nasal tract > 5 rat Pema ioeiy nue (CIES deposited mainly Hhom hey fers cono ne beat oa snc or-bue Cd (B Casd than | micron penetrate into the alveolar sacs and absorbed into the blood 3. Water solubility ee MEL use USI b Amc E-toU Tera iose re ele ceo cele mba lat HERE VM Tete em fina tto eso LOI NSN RIAU reach the bronchioles to alveolitrachea Airway anatomy 7 . Hecegg@nated blond) 1) Celgene oad ONG Alveolus © diffusion distance: ~20 mm total gas exchange area: ~80 m2PACA Ko) LiN, bronchial tree e diffusion distance blood/air: ~20 mm ¢ total exchange gas exchange area: ~80 m2a Te aries rio ME Eels) g ECO 1. Condition of the skin: Stratum corneum serves as the main lle eA WY ono ecemmnececnoerlosouunomyil Brest te PAS suelo iinaerstitalons This represents the rate at which a particular drug penetrates the skin 3. Body region aN Toe t cies (oem UICC MON a LEDUC LU TREC eos econ Constye- tbe CoN Bi yeRo loli The more lipid soluble the drug is the more it will be absorbed 5. Skin hydrationRate of Absorption The rate of absorption may be of toxicological importance because it is a major determinant of the peak plasma concentration and, therefore, the likelihood of acute toxic SiGe be So Momo cue BiKOe MRM Sm LTO Y skin into the general circulation involves movement across cell SME OR ST REMC RO meme Aat| molecule down a concentration gradient is the most important mechanism. Lipid-soluble molecules tend to cross cell membranes easily and are absorbed more rapidly than water-soluble ones. The gut wall and lungs provide a large and permeable surface area and allow rapid absorption; in contrast the skin is relatively impermeable and even highly lipid- soluble chemicals can enter only slowlyGUstep ited Celso) [tly Ubtne-reCebe-trRe else (omely ene erml ice. TOXICRate of Distribution The rate at which a chemical may enter or leave a tissue may be limited by two factors: (i) the ability of the compound to cross cell membranes and (ii) the blood flow to the tissues in which the chemical accumulates. The rate of distribution of highly water-soluble compounds may Lemme Cea rome mS Coy mec tT Cem LCM ECT MIN COM Lei Pe CSE TEMAS eC o Com yer eo ld aoe oC Rele) not accumulate in adipose tissue. In contrast, very lipid-soluble. ONSEN Be OresSeeo Meiners un Eke distribution may low because they accumulate in adiy tissue, and their overall distribution rate may be limited blood flow to adipose tissueThe rate of distribution is indicated by the distribution rate constant, which is determined from the decrease in plasma concentrations in early time points after an intravenous dose. The rate constants refer to a mean rate of removal from the circulation and may not correlate with uptake into a specific tissue. Once an equilibrium has been reached between the general circulation and a tissue, any process which lowers the blood (plasma) concentration will cause a parallel ol ToISB MU mL aor ee ne TH COEETE ViCaaeleR om Leet 1. Blood flow Drugs are readily distributed to highly perfused tissue like brain, liver, and kidneys Va Tonite bam erenrieeL tos) Many drugs do not readily enter the brain due to the blood brain barrier BPy acerotmoticeltiyeg Acidic ears are bound to the most abundant plasma protein (albumin); while basic drugs bind to a-1- acid glycoprotein.4. Effect of pH The pH of the blood or tissue affect the ionization of the drug and thus its distribution Biya In old people, Protein binding and body water will decrease, thus increasing the concentration Com eteMelartem orem elias beste 6. Existence of storage sites: These include: Adipose tissue, plasma proteins, liver, kidneys, and boneDem Mee ia The extent of tissue distribution of a chemical depends: on the relative affinity of the blood or plasma compared with the tissues. Highly water-soluble compounds that are unable to cross cell membranes readily are largely restricted to extracellular fluid (about 13 L per 70 kg body weight). Water-soluble compounds capable of crossing cell membranes (e.g. avai pe Mt ecTeCe)D ETc M led hy eect LEM osET Loeb A water (about 41 L per 70 kg body weight).Lipid-soluble compounds frequently show extensive uptake into tissues and may be present in the lipids of cell membranes and adipose tissue. . A factor which may further complicate the plasma/tissue partitioning is that some chemicals bind reversibly to circulating proteins such as albumin (for acid molecules) and acid glycoprotein (for basic molecules).The extent and pattern of tissue distribution can be investigated by direct measurement of tissue concentrations in animals. Tissue feyLees elo ecTOCOLOTSMer- ToL MoLm reer tice mTeMOLtboetbe studies and, therefore, the extent of distribution in humans has to be determined based solely on the concentrations remaining in plasma or blood after distribution 1s complete.volume of distribution Chemicals appear to distribute in the body as if it were a single compartment. The magnitude of the chemical’s distribution is given by the apparent volume of distribution (V,).Volume of Distribution (V4) Volume into which a drug appears to distribute with a concentration equal to its plasma concentration after distribution is Cryo (aK) yv., = Amount of drug in body FP secbh? OLS OUT LEIS) LAs Concentration in Plasmawhen a chemical shows a more extensive reversible uptake into one or more tissues the plasma. oylec abet Ayton c Kee R EAL nm TE increase. For highly lipid-soluble chemicals, such as organochlorine pesticides, which accumulate in Eel holosem tts mm anew e) Elsner Meee tcoelee:Le ley Bre bal eese) CAE La ACUMEN Mca r tems) kilogram of body weight. This is not a real volume of plasma and therefore V, is called the apparent volume of distribution.It is an important parameter because extensive reversible distribution into tissues, which will give a high value of V,,, is associated with a low elimination rate and a long half-life . It must be emphasized that the apparent volume SMcreele vos \ mca corm R.ae tate) which the chemical has moved out of the site of measurement (the general circulation) into tissues, and it does not reflect uptake into any specific tissue(s).