4. absorption and toxicokinetics Flashcards
flu vaccines
We develop flu vaccines to match the known strains of influenza virus each year expected to be a problem.
disposition of a toxicant
Absorption, Distribution, Biotransformation, Elimination
-depends on the properties and dose of toxicant
Absorption
is the process of toxicants moving across cell body membranes and into the bloodstream or lymph system.
local
in a specific tissue
systemic
throughout the organism
Cell types are often:
• stratified epithelium of the skin • thin cell layers of epithelium of the lungs and gastrointestinal tract • the capillary endothelium (into and out of bloodstream) • cells in the target organ or tissue
Cell membranes are:
• Lipid bilayers made mostly of phospholipids • Full of proteins (integral membrane proteins, peripheral proteins, etc.) • Coated in carbohydrates on the exterior of the cell
Toxicants mostly diffuse through ____ before entering the _______.
tissues, bloodstream
Diffusion
net movement of molecules from an area of high concentration to low concentration
Transcellular diffusion
diffusion of toxicants through cells (therefore must pass through cellular membranes). This occurs if the cells are packed tightly with little space between them
Paracellular diffusion:
diffusion of toxicants in-between cells.
-via tight junctions
Passive transport
Diffusion, Filtration
Passive transport • Diffusion
- How most toxicants cross membranes
- Smallhydrophilictoxicantsmorethroughaqueouspores
- Small hydrophobic diffuse across lipid domains of membranes
- Most toxicants are somewhat large and vary in how lipophilic they are
- Their rate of transport correlates with their lipid solubility
Most toxicants are somewhat large and vary in how lipophilic they are
Their rate of transport correlates with their lipid solubility
Filtration
• When water flows across a porous membrane, small molecules
can move with it.
• Important for renal glomeruli in the kidneys
• Molecules smaller than albumin (~60 kDa) can pass through the pores
“Special” transport
Active transport, Facilitated diffusion, Xenobiotic (and other things…) transporters
Active transport
- Movement against gradients
- Can be saturated (i.e., can reach a maximum)
- Can have competitive inhibition (i.e., chemical antagonists, compounds carried by the same transporter)
- Requires energy..
Facilitated diffusion
Carrier mediated transport that does not require energy
Xenobiotic (and other things…) transporters
2 categories:
• ATP-binding cassette (ABC) transporters
• Largelyfunctionthroughactivetransport • Solutecarriers
• Largelyfunctionthroughfacilitativediffusion
endocytosis
-Larger toxicants can enter cells
• Common for large molecules
• e.g., Proteinaceous toxins such as Shiga
toxin (Stx), ricin, Botulinum toxin and cholera toxin (Ctx).
receptor-mediated endocytosis,
cells have receptors that recognize these proteins and pinch off some of the cell membrane to form a vesicle, which contains the protein.
outside of cell
• Protein toxins are usually heterodimers made of the toxin (α subunit) and multiple β subunits. The β subunits binds to membrane components and tricks the cell into taking in the toxin.
Main sites of absorption are:
- Gastrointestinal (GI) tract
- Lungs – usually gases, vapors of volatiles and aerosols
- Skin
Enteral administration
includes all routes involving the alimentary canal
• i.e., Sublingual, oral, rectal
Parental administration
includes all other routes • i.e., Injection
The Gastrointestinal (GI) tract is a major absorption site for environmental toxicants that enter the food chain
• small intestine absorbs nutrients from the gut into the bloodstream.
Relatively few toxicants are actively absorbed in the GI tract, therefore most absorb here via diffusion
There are however many different types of transporters involved in the uptake of nutrients and electrolytes that do not diffuse across membranes.
• Various transporters can move xenobiotics from the intestine to the bloodstream
Diffusion is proportional to the surface area (i.e., villi and microvilli) and the residency time
• Rate of absorbance of a toxicant increases the longer it stays in the intestine.
The major areas of the human gastrointestinal tract
liver, stomach, large intestine, small intestine
liver
• chemicals absorbed in the gut first go through the liver via the hepatic portal
• major site of metabolism
• target organ for many toxicants • Can extract toxicants and
excrete them into bile
stomach
• pH = 2 • May degrade toxicants (esp. proteins) • Low pH will help in the absorption of weak acids (e.g., the NSAID naproxen)
small intestine
• pH 6 to 7.5
• major area of nutrient
uptake
large intestine
• pH 6
• major area of water uptake
• Natural gut bacteria can
convert toxicants to different forms
Multidrug-resistant (MDR) and multiresistant drug (MRP) proteins
move xenobiotics out of cells.
The lungs are a major site of absorption fo
gases, vapors of volatile liquids and aerosols.
Gases and Vapors
• When inhaled, gas molecules diffuse from the alveoli space into the
blood until at equilibrium (uptake and removal are equal).
• Blood distributes the gases throughout the body and transfers it to
tissues.
• Now blood will pick up more gas at the lungs.
• Will keep happening until the gas is in equilibrium in the lungs,
blood and tissue.
Aerosols
Deposition of aerosols depends on the size
• ≥5μm deposited in the nasopharyngeal region
• ~2.5μm deposited in lungs
• ≤1μm may penetrate alveolar sacs, and potentially enter the blood
Gasses and vapors can be inhaled and readily pass into the bloodstream.
Each gas/vapor has it’s own properties
that indicate how quickly equilibrium is reached
Aerosols and Particulates
Aerosol = small droplet of liquid Particulate = small chunk of solid matter
• Particles are swept out by cilia
• Only 20% cleared out in one day… some
particles can hang around for months or years
• e.g., asbestos
>5 um stick here
2.5 um stick here
<1 um make it here
• Toxicant absorption through the skin
• The skin is relatively impermeable, so it is a minor route of toxicant absorption.
• All toxicants passively diffuse through the stratum corneum
• Toxicants must pass through several cell layers (and thus membranes) in the upper
epidermis to get to the blood stream.
Absorption through the skin can increase by:
- Damage to the stratum corneum
- Increased hydration
- Increased blood flow
- Size of toxicant (small ones increase
absorption)
Toxicant storage through the body
Different toxicants can get bound in different storage sites in the body depending on their chemistry. Storage sites aren’t always the target of toxicity!
toxicant storage: Blood
• Albumin is an abundant protein in the blood
• Its ‘normal’ function is to transport fats, hormones, and other
hydrophobic compounds
• Albumin can bind toxicants
• This is a reversible process (think about the warfarin
example)
toxicant storage: liver and kidney
Involved in the metabolism and excretion of toxicants (more on this later), but can also be a site of storage
toxicant storage: fat
Most organic toxicants are hydrophobic, so will accumulate in adipose tissue
• But can be released later
dieldrin poisoning.
When the fat reserves were mobilized to produce eggs, the dieldrin was released and reached toxic levels.
In most animals, release from fat deposits can be a significant source of toxicants in the blood.
blood brain barrier
can keep many toxicants out of the brain because:
• The capillaries in the brain have few pores that limits diffusion.
• Thecapillaryendothelialcellshavemdrtransportersthatcanpump unwanted chemicals back into the bloodstream.
• Interstitial fluid has few proteins, which makes paracellular transport limited.
• Note that this evolved to keep natural toxins out of our brains!
• Veryhydrophobicnon-ionic chemicals can readily pass the BBB though…
• Just like the caffeine that goes directly to my brain!
• The BBB is poorly developed in infants, which also makes them more susceptible to toxicants
Toxicokinetic modelling
tries to put math functions to the disposition of a compound.
• Basically trying to ask: based upon the chemical characteristics of a molecule, where will it end up in the body?
“Classic”toxicokinetics
assume the compounds move through the body as if there were only 1 or 2 compartments.
• One-compartment model
linear relationship when the Log plasma concentration is plotted over time.
• Can describe toxicants that come to equilibrium really quickly
Can estimate the half-life of elimination (T1/2), which is the time required for the blood or plasma chemical concentration to decrease by one-half.
Two-compartment models
central tissues (involved in elimination of the chemical) and peripheral tissues (come to equilibrium much slower) • Gives a curved line when the log plasma concentration is plotted over time
Physiologically based toxicokinetic models
represent a series of mass balance equations that describe each tissue.
