Download - Disposition of Chemicals
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Absorption
Distribution
Metabolism
Excretion
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The most common means of entry of chemical compounds include:
Digestive Tract ( Oral )Lungs or Gills ( Inhalation )Skin ( Dermal )Other Routes
Intraperitoneal, intramuscular, subcutaneous, intravenous
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Absorption necessarily involves the passage of compoundsacross membranes. Therefore, membrane structure andtransport processes are important issues.
Absorption is the process whereby toxicants gain entrance tothe body. Ingested and inhaled materials, nonetheless, areconsidered outside the body until they cross the cellularbarriers of the gastrointestinal tract or the respiratory system.To exert an effect on internal organs a toxicant must beabsorbed, although such local toxicity as irritation, may occur.
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Processes of absorption:Filtration
Passive Diffusion
Active TransportFacilitated DiffusionPhagocytosis/Pinocytosis
Several factors affect the likelihood that a foreign chemical willbe absorbed.route of exposure.
concentration of the substance at the site of contact.chemical and physical properties of the substance.
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Everything in solution in the plasma getsfiltered into the primary urine. Unlessactively reabsorbed, everything that isfiltered will ultimately be excreted.Bearing in mind that the filtration fractionis 20%, this means that at most 20% of anysubstance in the blood will be excreted in asingle pass through the kidney. The bloodrepeatedly circulates back to the rest of thebody and then back to the kidney again.
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Facilitated diffusion is thediffusion of a substance across amembrane. It is "facilitated"because a transport protein inthe membrane enhances the
transport of the substance acrossthe membrane.Depends upon diffusion throughphospholipid bilayer
Must be a conc. gradient across
membraneCompound must be lipidsolubleCompound must be in non-ionized state
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Absorption of compounds by diffusion will followFicks Law
Rate of diffusion = KA (C2 C1)
d*D* = Diffusion coefficient which is characteristic to the
medium
The concentration gradient will normally be maintained andan equilibrium will not be reached. The concentration onthe inside of the membrane will be continually decreasingas a result of ionization, metabolism, and distribution toanother compartment.
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Active transport uses energy (in theform of ATP), and materials flowagainst the concentration gradient.a specific membrane carrier systemis required
the process may be saturated at highsubstrate concentrationssubstrates may compete for uptake
5-fluorouracil, an anticancerdrug, is absorbed by thepyrimidine transport system
Lead is absorbed by the calciumtransport system
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Digestive TractThis is one of the most important sites of absorptionbecause many substances are in the food that we eat; alsofor drugs we take
If a compound is a weak acid or a weak base, the compound ismainly absorbed from the part of the digestive tract in which thecompound exists in the non-ionized form (the most lipid solubleform).
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The amount of the chemical that enters thesystemic circulation after oral administrationdepends upon:
The amount absorbed into digestive tract cellsThe amount metabolized (bio-transformed) bydigestive tract cells
The amount extracted by the liver termed thefirst pass effect
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Gases, vapors of volatile compounds, particulatematter
For compounds with a low solubility in blood the rate of transfer from air (in alveolus) to blood will be mainlydependent on blood flow (perfusion limited)For compounds with a high solubility in blood the rate of transfer from air (in alveolus) to blood will be mainlydependent on respiration rate (ventilation limited)
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Particulate matter
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Skin is not very permeable but somecompounds can penetrate skin (nerve gases,
some insecticides, carbon tetrachloride)Compounds must pass through epidermis,sweat/sebaceous glands or hair follicles; mostmovement is through epidermis
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Compounds are distributed to various tissues by theplasmaDistribution is a very complex process and the finaldistribution of a particular compound dependslargely on the affinity of the compound for varioustissues
Important Point!
The site of highest conc. of acompound is not necessarily the site of toxic action
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Plasma Proteins There are a number of proteins in
plasma that can reversibly bind variouschemical compounds
Most compounds that bind to plasmaproteins bind to albumin albumin has6 different binding regions
Environmental chemical and drugscan compete with and displace
endogenous compounds that arebound to plasma proteins, or witheach other, for binding sites.
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Liver and Kidney These two organs
concentrate more chemical
compounds than all otherorgans combined
Ligandin (binds weak acids)and Metallothionein (binds
metals) are two proteinsthat concentrate in the liverand kidneys
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Adipose Tissue Many toxic compounds are
highly lipophilic and theyaccumulate in adipose tissue
by dissolution in neutral fats(triglycerides) Adipose tissue can constitute
~ 50% of body weight inobese people and ~ 20% of
body weight in lean people Issue with migrating and
hibernating animals,significant weight loss
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Bones Compounds such as
fluoride, lead, andstrontium accumulate inbone
90% of lead in the body iseventually found in theskeleton
Fluoride displaces OH- Lead and strontium displaces
Ca++
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Central Nervous System Compounds entering the Central Nervous
System must pass the Blood-Brain Barrier Increased lipid solubility increases rate of
chemical entry into CNS while ionizationdecreases rate of entry (passive diffusion)
Some chemical compounds (very few)enter the CNS by carrier transportprocesses, ex. Methylmercury combineswith cystein forming a compound similarto methionine and then compound isactively transported into CNS
Blood Brain Barrier is not fully formed ininfants therefore some compounds likemorphine and lead are much more toxic toinfants than to adults
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Fetus Many compounds (especially
lipophilic compounds) can crossthe placenta
Placenta has metabolizing (bio-transformation) ability so somecompounds might not reach fetus
Fetus has little fat so fetus does notaccumulate large amounts of lipophiliccompounds
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Excretory Pathways:
Kidney (Urinary Excretion)Digestive Tract (Fecal Excretion)LungsOthers
Sweat Hair Milk
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Urinary ExcretionCompounds with high lipid solubility (non-ionized) willbe reabsorbed from the nephron back into the plasmaCompounds that are ionized will tend to be excreted
Bases are excreted better at a lower urinary pH Acids are excreted better at a higher urinary pH
Ex. Phenobarbital poisoning (weak acid) treated using sodiumbicarbonate to increase urinary pH
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Because some kidney functions are not fully developed at birth,some compounds are excreted more slowly in infants than inadults
Ex. Penicillin excreted at 20% rate of adult
Proximal tube cells reabsorb small proteins Cadmium andmercury attached to metallothionein enter proximal tube cells,remain in cells and kill cells
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Fecal ExcretionSome percentage of chemicals ingested passthrough digestive tractunabsorbed The biliary route is themost importantmechanism for excretionfrom digestive tract
Bile production occurs in theliver, bile flows to bile ductand then to small intestine
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Factors that affect excretion by digestive tract Molecular weight and charge of the chemical compound Animal species
MW of 300 or more give significant excretion through bile.The exact cutoff varies with species
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Charge on compound If the compound stay ionized at pH of small intestine little of the
compound will be reabsorbed If the compound becomes non-ionized at pH of small intestine then
compound will be reabsorbed, called Enterohepatic Circulation
Enterohepatic Circulation Microflora in the gut can metabolize the chemical back to a lipid
soluble form chemical then reaborbed
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LungsChemical with lowsolubility in blood fast
excretionChemical with highsolubility in blood slowexcretionParticulate matterinvolved with ciliaryescalator or
macrophages
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Other RoutesSweat and Saliva MinorimportanceHair some metals like
mercuryMilk lipophilicsubstances and somemetals such as lead,transfer from mother to
infant Can also be tansfer
through consumptionof dairy products
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