Lecture 5: Absorption and Distribution Flashcards
Disposition
Absorption- How it gets in the body
Distribution -Where it goes in the body
Biotransformation- What the body does with it
Elimination- How it leaves the body
What does disposition depend on?
on the properties of the toxicant
- i.e., target tissue, hydrophilic vs. hydrophobic, size
- Also depends on the dose, age, size and genetics!
Absorption
when toxicants cross membranes and enter the bloodstream or lymphatic system
How do toxicants enter the body?
Most part
Ingestion
Dermal
Inhalation
Describe how toxicants get ingested
go into stomach, intestines anything that gets absorbed goes thru hepatic portal which shunts everything that gets absorbed into liver before going into general circulation
Liver- place of detoxification
tissues
unique ‘compartments’ in the body
Toxic effects may be__________
may be local (in a specific tissue) or systemic (throughout the organism).
Describe the cell membrane composition what can go thru what cant
Made up of a phospholipid bilayer with many transmembrane proteins (i.e., integral proteins).- small lipid soluble compounds can diffuse straight thru not hydrophilic ones
Are semipermeable.
The proteins can form pores and transporters to move larger compounds or hydrophilic compounds.
Lipophilic compounds can diffuse across the membrane.
Toxicants________through tissues before entering______
Toxicants often need to diffuse through tissues before entering the bloodstrea
Diffusion
is the net movement of molecules from an area of high concentration to low concentration.
- i.e., down a concentration gradient.
How most toxicants cross membranes
Transcellular diffusion
diffusion of toxicants through cells (must pass through cellular membranes). Often occurs if the cells are packed tightly with little space between them.
MOST TOXICANTS MAKE IT TO THE BODY THRU THIS TYPE OF DIFFUSION
Paracellular diffusion
diffusion of toxicants in between cells.
What prevents paracellular diffusion?
Epithelial cells have tight junctions which prevent this diffusion, which makes thing go thru the cell which allows for better control
What types of molecules can pass thru the membrane? large or small non polar or polar; do they require channels
Small hydrophilic toxicants can move through aqueous pores (i.e., aquaporins- proteins that allow h20 to move through membrane bc they cant move thru alone)
Small hydrophobic diffuse across lipid bilayer of membranes
How do toxicants vary
in how lipophilic they are. *** (vary how lipid soluble they are)
• Rate of transport across membranes correlates with their lipid solubility
Super lipophilic vs less
Super lipophilic= move across super fast
less lipophilic= slower
Filtration
When blood plasma is forced out of capillaries through pores because of pressure, small molecules can move with it. (forced movement of water and other small compounds out of the blood and into the tissues)
Big molecules like albumin and red blood cells stay in blood
i.e., Important process in the glomeruli of the kidneys
Active transport
Requires ATP)
Movement against concentration gradients
Transporters can be saturated (i.e., can reach a maximum)
Can have competitive inhibition (i.e., chemical antagonists, compounds carried by the same transporter)
Facilitated diffusion
Carrier mediated transport that does not require energy
Transmembrane protein required to move across membrane
ATP-binding cassette (ABC) transporters
- Active transport
Involved in moving things out of the cell
If toxicants make into intestinal epithelial cells the transporters can grab them and kick them out
e.x. MDR1, MRP, BSEP, BCRP
Solute carriers
General term for transporting larger compounds
Facilitated diffusion (down concentration gradient)
e.x., OATP, OAT, OCT, PEPT
What is the most effective way of producing ATP
produced most efficiently through aerobic metabolism (via oxidative phosphorylation that occurs in the mitochondria).
Fish need to maintain the production of ATP by increasing their “breathing” to maintain sufficient O2 delivery to tissues. Some of this ATP is needed to fuel active transporters to move the toxicants out of the cells and the body!
How are toxicants removed from our body?
REMOVING TOXICANTS FROM OUR BODY REQUIRES ATP REQUIRES ACTIVE TRANSPORT THAT CAN LEAD TO AN OVERALL INCREASE OF METABOLIC RATE IN ANIMALS
endocytosis
How Larger toxicants enter
Cell membrane forms vesicle and carries hydrophilic compounds across cell membrane
receptor-mediated endocytosis,
cells have receptors that recognize certain proteins and form a vesicle, which contains the protein
Main sites of absorption are:
- Gastrointestinal (GI) tract
- Lungs
- Skin
Enteral administration
includes all routes involving the alimentary canal • i.e., Sublingual, oral, rectal
Parental administration
includes all other routes
• i.e., Injection
What is the major absorption site for toxicants?
Small intestine absorbs nutrients from the gut into the bloodstream.
The Gastrointestinal (GI) tract i
Relatively few toxicants are actively transported in the GI tract, therefore most absorb here through diffusion.
There are many different types of transport proteins involved in the facilitated diffusion of nutrients and electrolytes.
Can also move xenobiotics from the intestine to the blood.
Diffusion is proportional to the surface area (i.e., villi and microvilli) and the residency time.
Probability of absorbing a toxicant increases the longer it stays in the intestine.
How do gases and vapors get absorbed?
When inhaled, gas molecules diffuse from the alveoli into the blood until at equilibrium (uptake and removal are equal).
Blood distributes the gases throughout the body and where they are transferred to target tissues gases get removed from blood
Then blood will pick up more gas at the lungs. (partial pressure gradient favours this)
Will keep happening until the gas is in equilibrium throughout the body.
WAY OUR BODIES ARE DESIGNED RLY FAVOURS ABSORPTION OF VAPORS IN THE LUNGS
Aerosols
Deposition where they end up in body) of aerosols depends on the size.(same thing with particulate matter)
small droplet of liquid
GASES AND VAPOR GETS ABSROBED RLY EASILY AND AERSOL AND PARTICULATES DEPEND ON SIZE
TRUE OR FALSE
TRUE
Particulate
small chunk of solid matter
are swept out by cilia – If we are breathing in a lot of particulate matter we aren’t clearing it out at the same rate we are breathing it in
If you’ve been exposed to rly dusty conditions the taste of that dust stays in mouth
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 and then must pass through several cell layers (i.e., many membranes) in the upper epidermis to get to the blood stream.
hydrated stratum corneum
is the rate-determining barrier of skin. Thicker on palms and soles than on arms, back, legs, etc.
Toxicant storage through the body
Different toxicants can be stored at different sites in the body depending on their properties. Storage sites aren’t always the target of toxicity!
Blood
Albumin is an abundant protein in the blood
Its ‘normal’ function is to transport fats, hormones, and other hydrophobic compounds.
Albumin can also bind toxicants.
This is a reversible process (think about the warfarin example).
Liver and Kidney
• Involved in the metabolism and excretion of toxicants, but can also be a site of storage.
Fat
Many toxicants are hydrophobic, so can accumulate in adipose tissue.
• But… then can be released later.
*especially if they have really long half life in the body
Blood brain barrier
can keep many toxicants out of the brain because
- The capillaries in the brain have few pores, which can limit diffusion.
- The capillary endothelial cells have MDR transporters that can send unwanted compounds back into the bloodstream.
- Paracellular diffusion limited(transcellular can be more regulated).
this evolved to keep natural toxins out of our brains!
What can pass thru the blood brain barrier?
Very hydrophobic non-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.
