Toxicokinetics :- Absorption

By : yusur alani2016

Toxicokinetics

. Is the quantitation of the time courseof toxicant in the body durnig theprocesses of absorptiondistribution,metabolism, andexecretion , ADME.

Toxicokinetics• Toxicokinetics describes how the body handles a toxicant,as a function of dose and time, in terms of ADME:• The rate of chemical absorption from the site of application into the blood stream (Absorption)• The rate and extent of chemical movement out of blood into the tissue (Distribution)• The rate and extent of chemical biotransformation into metabolites (i.e. Metabolism)• The rate of chemical removal from the body (Excretion)

Absorption of toxicants

• Absorption is the transfer of the parent chemicalfrom the site of administration into the generalcirculation• Absorption is also used to describe the extent towhich the radioactivity from a radiolabelledchemical is transferred from the site ofadministration into the excreta and/or expired air.• To exert a toxic effect on internal organs atoxicant must be absorbed, although such localtoxicity as irritation, may occur.

Absorption• Transfer of chemicals from thegut lumen, lungs, or skin intothe general circulation involvesmovement across cellmembranes, and simplepassive diffusion of theunionized molecule, down aconcentration gradient is themost important mechanism.• Lipid-soluble moleculestend to cross cellmembranes easily and areabsorbed more rapidlythan water-soluble ones.

• IT is often useful to determine how much of thetoxicant actually penetrates the membrane barriers (e.g skin or GIT) and gets into the blood stream.• The area under the curve (AUC) of theconcentration- time profiles for oral or dermalroutes is compared with the AUC for IV ROA.• The ratio of these (AUC) values is absolutebioavaiability.

Extent of absorption

BioavailabilityIs used to describe the extent and rate of absorption for a xenobiotic,which enters the systemic circulation from the exposure site.

F = AUCoral / AUCIV

First pass effect• A phenomenon oftoxicant metabolismwhereby concentrationof a drug is greatlyreduced before itreaches the systemiccirculation, is termedfirst-pass metabolismor pre-systemicmetabolism.

Rate of absorption• The rate of absorption may be of toxicological importancebecause it is a major determinant of the peak plasmaconcentration and, therefore, the likelihood of acute toxiceffects.• Transfer of chemicals from the gut lumen, lungs, or skin intothe general circulation involves movement across cellmembranes, and simple passive diffusion of the unionizedmolecule, down a concentration gradient is the mostimportant mechanism.• Lipid-soluble molecules tend to cross cell membranes easilyand are absorbed more rapidly than water-soluble ones.

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 effects.

Types of transport• 1- Simple diffusion

• 2- Facilitated diffusion

• 3- Active transport

• 4-Endocytosis(Pinocytosis&phagocytosis)

• 5- Filtration

Simple diffusion• Chemicals traverse from regions ofhigher concentration to regions oflower concentration• Transport is not saturable .

• No structural specificity.

• No energy requirement.

1-Carrier protein mediated transport2-Not occur againstconcentration or electricalGradient

3- Does not require ATP

Facilitated diffusion

• E.g lead ,thallium and paraquat herbicideare transported across the intestinal wallby active transport system.

Active transport

Pinocytosis

Pinocytosis :In pinocytosis, fluid or particlesare engulfed by a cell.The cell membrane , enclosesthe fluid or particles, then fusesagain, forming a vesicle thatlater detaches and moves tothe cell interior.Energy expenditure is required.

Phagocytosis

• Phagocytosis:large particlessuspended in theextracellular fluid areengulfed and eithertransported into cells orare destroyed within thecell.

filtration

• filtration involves themovement of waterand solutes across thecell membrane due tohydrostatic pressure

Routes of exposure

• 1. Ingestion• 2. Inhalation• 3. Dermal• 4. Intravascular• 5. Ophthalmic

Gastric absorption

• Absorption of toxicantscan take place along theentire GI tract, even inthe mouth and therectum.

• Absorption of toxicsubstances in thedigestive tract occursprimarily in the smallintestine.

Gastrointestinal absorption

• Absorption of a toxicant from the GI tract depends on its• physical properties, including lipid solubility, its dissolution rate, , particlesize etc.• It is also affected by the local factors in GI tract:• pH• Motility.• Presence of Food.• Digestive enzymes.• Microbial flora.

Gastrointestinal absorption

• Weak acids and bases will be absorbed by simplediffusion to a greater extent in the part of the GI tract inwhich they exist in the most lipid-soluble (non-ionized)form.• The stomach, having high acidity (pH 1-3),is asignificant site for absorption of weak organicacids,which exist in nonionised and lipid soluble form.• Chemically, the stomach acidity may break downsome substances.

• Organic bases would be absorbed more readly in thesmall intestine(Ph 5.0 to 8.0).

• Small lipid soluble substances generally enter themucosal epithelial cells by passive diffusion.

• Particulate toxicants can be absorbed via vesiculartransport ,either by pinocytosis or phagocytosis.

• Highly hydrophobic compounds may be absorbed into

• the lymphatic system via chylomicrons and drained into

• venous circulation near the heart

Gastric absorption

• Some xenobiotics are absorbed by the samespecialised transport systems, thereby leading topotential competition or interaction (Iron inhibits leadand cadmium intestinal uptake due to sharedabsorption mechanism; conversely, toxic metals mayinhibit essential element absorption).

• 5-fluorouracil absorbed by the pyrimidine transportsystem.• thallium by iron transport system.

• Lead by calcium transporter

.Chemicals given via the gastrointestinal tract may

be subject to a wide range of pH values andmetabolizing enzymes in the gut lumen or gut wall,toxicant may biotransformed to a more toxicproduct e.g the formation of carcinogenicnitrosamines from non carcinogenic amines.

Respiratory absorption

• Lungs have between 30and 100 m2 of surfacearea, large blood flow of2000 km of capillary beds;thin physical chemicalbarrier between air andblood of 0.8 ~m - nicebarrier for toxicants.

• gases and vapours comeinto equilibrium with bloodin the alveolar capillariesalmost instantaneously.

Respiratory tract absorption

. Gases and particles, which are water-soluble(and thus blood soluble), will be absorbed moreefficiently from the lung alveoli.Water-soluble gases and liquid aerosols canpass through the alveolar cell membrane bysimple passive diffusion.The absorption of airborne particles isdependent upon particle size ,regardless ofsolubility.

Respiratory tract absorption

• Large particles (>5 μM) are generallydeposited in the nasopharyngeal region withlittle absorption.• Particles 2-5 μM can penetrate into thetracheobronchial region.• Very small particles (<1 μM) are able topenetrate deep into the alveolar sacs wherethey can deposit and be absorbed.

Respiratory tract absorption

• Pulmonary macrophages exist on thesurface of the alveoli.• They are not fixed and not a part of thealveolar wall.• They can engulf particles just as they engulfand kill microorganisms.• Some non-soluble particles are scavengedby these alveolar macrophages and clearedinto the lymphatic system .

Examples of Toxicant Gases or Volatile Liquids

1. Sarin gas—chemical warfare agent ,that causesexcessive neuronal excitation, convulsions, seizures,tearing, salivation, suffocation, and death throughinhibition of acetylcholinesterase2. Carbon tetrachloride—volatile liquid used widely asa cleaning agent and refrigerant, currently banned—greenhouse gas and carbon tetrachloride can bebioactivated in the liver to produce a potenthepatotoxin3. Benzene—largely found in crude oil, but also foundin tobacco smoke and used to be found in glues,paints, and detergents—benzene metabolism leadsto bioactivated carcinogens that cause leukemia

Non-absorbed foreign material can also cause severetoxic reactions within the respiratory system. This maycause:• 1- chronic bronchitis.

• 2- alveolar breakdown (emphysema).

• 3- fibrotic lung disease.

• 4- lung cancer.

• In some cases, the toxic particles can kill the alveolarmacrophages, which results in a lowering of the bodies'respiratory defense mechanism.

Dermal absorption

• The epidermis (andparticularly the stratumcorneum) is the only layerthat is important inregulating penetration of askin contaminant.

Dermal absorption

• The skin is a complex, multilayer tissue. For thisreason, it is relatively impermeable to most ions aswell as aqueous solutions.

• It represents, a barrier to most xenobiotics.

• Some notable toxicants, however, can gain entryinto the body following skin contamination

Dermal absorption

• Toxicants move across the stratum corneum by passive diffusion.

• water soluble ,(polar) compounds appear to diffuse through theouter surface of the hydrated keratinized layer .

• Lipid-soluble ,(nonpolar )dissolve and diffuse through the lipidmaterial between the keratin filaments .

• Once the substance penetrates through the Stratum corneum ,itenters lower layers of the epidermis(dermis and subcutaneoustissues.

• toxicant then can readily enter the circulation via the large numberof venous and lymphatic capillaries in the dermis.

Dermal absorption

• In addition to the stratum corneum, smallamounts of chemicals may be absorbedthrough the sweat glands, sebaceousglands, and hair follicles.

Exampels :

• The neurological warfare agent, Sarin, readily passesthrough the skin and can produce quick death toexposed persons.• Several industrial solvents can cause systemic toxicityby penetration through the skin .• e.g carbon tetrachloride penetrates the skin andcauses liver injury.• e.g hexane can pass through the skin and cause nervedamage.

Example:

• Praben esters(used in the majority of skin carecosmetics ) are absorbed through the skin, andincrease female breast cancer incidence ,interferewith male reproductive function ,and to influencedevelopment of malignant melanoma .

Intravascular

• Intravenous (I.V)•INTRAMUSCULAR(I. M)•SUBCUTANEOUS (S.C)•Intraperitoneal (I.P)

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