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.
http://www.eoearth.org/article/Organ_systems_and_organshttp://www.eoearth.org/article/Organ_systems_and_organs


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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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Disposition of Chemicals

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