Disposition of Chemical
Compounds
Four Phases To Disposition of
Chemical Compounds




Absorption of Chemicals into the Body
Distribution of Chemicals within the
Body
Metabolism of Chemicals within the
Body
Excretion of Chemicals from the Body
Absorption of Chemical
Compounds

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
Absorption - Continued

Absorption necessarily involves the
passage of compounds across
membranes. Therefore, membrane
structure and transport processes are
important issues.
Absorption - Continued
Transport Across Membranes






Filtration
Passive Diffusion
Active Transport
Facilitated Diffusion
Phagocytosis/Pinocytosis
Absorption - Continued

The most common transport process for
absorption of chemical compounds in
passive diffusion.




Depends upon diffusion through
phospholipid bilayer
Must be a [ ] gradient across membrane
Compound must be lipid soluble
Compound must be in non-ionized state
Absorption - Continued

Absorption of compounds by diffusion will
follow Fick’s Law

Rate of diffusion = KA (C2 – C1)
d
The concentration gradient will normally be
maintained and an equilibrium will not be reached.
The concentration on the inside of the membrane
will be continually decreasing as a result of
ionization, metabolism, and distribution to another
compartment.
Absorption - Continued

Passive diffusion relies on dissolution of the
compound in the lipid component of the membrane
and therefore only lipid soluble (lipophilic)
compounds will pass through the membrane.




Lipid Solubility measured by Octanol – Water Partition
Coefficient (Kow)
Lipophilic compounds have a Kow = 100 to 1,000,000
Log Kow value is used so Kow = 2 to 6 for lipophilic
compounds
Very lipophilic compounds --- Kow > 6 may get stuck in
membrane and not be absorbed as readily as Kow 2 to 6
compounds
Absorption - Continued

Active and Facilitated Transport:



a specific membrane carrier system is required
the process may be saturated at high substrate
concentrations
substrates may compete for uptake


5-fluorouracil, an anticancer drug, is absorbed by the
pyrimidine transport system
Lead is absorbed by the calcium transport system
Absorption – ContinuedCompartments
Sites of Absorption

Digestive Tract

This is one of the most important sites of
absorption because many substances are in the
food that we eat; also for drugs we take


If a compound is a weak acid or a weak base, the
compound is mainly absorbed from the part of the
digestive tract in which the compound exists in the nonionized form (the most lipid soluble form).
Handout for Students!
Absorption – ContinuedAcids and Bases
Digestive Tract - Continued

The amount of the chemical that enters
the systemic circulation after oral
administration depends upon:



The amount absorbed into digestive tract
cells
The amount metabolized (bio-transformed)
by digestive tract cells
The amount extracted by the liver –
termed the “first pass effect”
Lungs

Gases, vapors of volatile compounds,
particulate matter


For compounds with a low solubility in blood – the
rate of transfer from air (in alveolus) to blood will
be mainly dependent 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 mainly dependent on respiration rate
(ventilation limited)
Lungs - Continued

Particulate matter
Skin

Skin is not very permeable but some
compounds can penetrate skin (nerve
gases, some insecticides, carbon
tetrachloride)

Compounds must pass through epidermis,
sweat/sebaceous glands or hair follicles;
most movement is through epidermis
Distribution of Chemical
Compounds With Body


Compounds are distributed to various tissues
by the plasma
Distribution is a very complex process and the
final distribution of a particular compound
depends largely on the affinity of the
compound for various tissues

Important Point! – The site of highest [ ] of a
compound is not necessarily the site of toxic
action
Absorption – ContinuedCompartments
Distribution - Continued

Storage of Compounds

Plasma Proteins


There are a number of proteins in plasma that can
reversibly bind various chemical compounds
Most compounds that bind to plasma proteins bind to
albumin – albumin has 6 different binding regions


Environmental chemical and drugs can compete with and
displace endogenous compounds that are bound to plasma
proteins
Environmental chemicals and drugs can compete with each
other for binding sites and displace eachother
Distribution - Continued

Storage of Compounds

Liver and Kidney


These two organs concentrate more chemical
compounds than all other organs combined
Ligandin (binds weak acids) and
Metallothionein (binds metals) are two proteins
that concentrate in the liver and kidneys
Distribution - Continued

Storage of Compounds

Adipose Tissue



Many toxic compounds are highly lipophilic and
they accumulate in adipose tissue by
dissolution in neutral fats (triglycerides)
Adipose tissue can constitute ~ 50% of body
weight in obese people and ~ 20% of body
weight in lean people
Issue with migrating and hibernating animals,
significant weight loss
Distribution - Continued

Storage of Compounds

Bones

Compounds such as fluoride, lead, and
strontium accumulate in bone



90% of lead in the body is eventually found in the
skeleton
Fluoride displaces OHLead and strontium displaces Ca++
Distribution - Continued

Storage of Compounds

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 ionization decreases rate of entry (passive
diffusion)
Some chemical compounds (very few) enter the CNS by
carrier transport processes, ex. Methylmercury combines
with cystein forming a compound similar to methionine
and then compound is actively transported into CNS
Blood Brain Barrier is not fully formed in infants – therefore
some compounds like morphine and lead are much more
toxic to infants than to adults
Distribution - Continued

Storage of Compounds

Fetus

Many compounds (especially lipophilic
compounds) can cross the placenta


Placenta has metabolizing (bio-transformation) ability
so some compounds might not reach fetus
Fetus has little fat so fetus does not accumulate
large amounts of lipophilic compounds
Excretion of Chemical
Compounds

Excretory Pathways:




Kidney (Urinary Excretion)
Digestive Tract (Fecal Excretion)
Lungs
Others



Sweat
Hair
Milk
Excretion - Continued

Urinary Excretion


Compounds with high lipid solubility (nonionized) will be reabsorbed from the
nephron back into the plasma
Compounds 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 sodium bicarbonate to increase urinary pH
Excretion - Continued

Urinary Excretion

Because some kidney functions are not fully
developed at birth, some compounds are excreted
more slowly in infants than in adults


Ex. Penicillin – excreted at 20% rate of adult
Proximal tube cells reabsorb small proteins –
Cadmium and mercury attached to metallothionein
enter proximal tube cells, remain in cells and kill
cells
Excretion - Continued

Fecal Excretion


Some percentage of chemicals ingested
pass through digestive tract unabsorbed
The biliary route is the most important
mechanism for excretion from digestive
tract

Bile production occurs in the liver, bile flows to
bile duct and then to small intestine
Excretion - Continued

Fecal Excretion

Factors that affect excretion by digestive
tract



Molecular weight of the chemical compound
Charge on the chemical compound
Animal species
Excretion - Continued

Fecal Excretion

Molecular weight of chemical

MW of 300 or more give significant excretion
through bile. The exact cutoff varies with
species
Excretion - Continued
Excretion - Continued

Fecal Excretion - Continued

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
Excretion - Continued
Excretion - Continued
Excretion - Continued

Lungs



Chemical with low solubility in blood – fast
excretion
Chemical with high solubility in blood –
slow excretion
Particulate matter involved with “ciliary
escalator” or macrophages
Excretion - Continued

Other Routes



Sweat and Saliva – Minor importance
Hair – some metals like mercury
Milk – lipophilic substances and some
metals such as lead, transfer from mother
to infant

Can also be tansfer through consumption of
dairy products
Concept of Half-Life
Half-Life With One
Compartment Model
Half-Life With Multiple
Compartment Model
Multiple Dosing of Compounds