Lecture 5: Absorption and Distribution

Question 1

Disposition

Answer 1

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

Question 2

What does disposition depend on?

Answer 2

on the properties of the toxicant

• i.e., target tissue, hydrophilic vs. hydrophobic, size
• Also depends on the dose, age, size and genetics!

Question 3

Absorption

Answer 3

when toxicants cross membranes and enter the bloodstream or lymphatic system

Question 4

How do toxicants enter the body?

Answer 4

Most part
Ingestion
Dermal
Inhalation

Question 5

Describe how toxicants get ingested

Answer 5

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

Question 6

tissues

Answer 6

unique ‘compartments’ in the body

Question 7

Toxic effects may be__________

Answer 7

may be local (in a specific tissue) or systemic (throughout the organism).

Question 8

Describe the cell membrane composition what can go thru what cant

Answer 8

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.

Question 9

Toxicants________through tissues before entering______

Answer 9

Toxicants often need to diffuse through tissues before entering the bloodstrea

Question 10

Diffusion

Answer 10

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

Question 11

Transcellular diffusion

Answer 11

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

Question 12

Paracellular diffusion

Answer 12

diffusion of toxicants in between cells.

Question 13

What prevents paracellular diffusion?

Answer 13

Epithelial cells have tight junctions which prevent this diffusion, which makes thing go thru the cell which allows for better control

Question 14

What types of molecules can pass thru the membrane? large or small non polar or polar; do they require channels

Answer 14

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

Question 15

How do toxicants vary

Answer 15

in how lipophilic they are. *** (vary how lipid soluble they are)

• Rate of transport across membranes correlates with their lipid solubility

Question 16

Super lipophilic vs less

Answer 16

Super lipophilic= move across super fast

less lipophilic= slower

Question 17

Filtration

Answer 17

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

Question 18

Active transport

Answer 18

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)

Question 19

Facilitated diffusion

Answer 19

Carrier mediated transport that does not require energy

Transmembrane protein required to move across membrane

Question 20

ATP-binding cassette (ABC) transporters

Answer 20

• 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

Question 21

Solute carriers

Answer 21

General term for transporting larger compounds

Facilitated diffusion (down concentration gradient)

e.x., OATP, OAT, OCT, PEPT

Question 22

What is the most effective way of producing ATP

Answer 22

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!

Question 23

How are toxicants removed from our body?

Answer 23

REMOVING TOXICANTS FROM OUR BODY REQUIRES ATP REQUIRES ACTIVE TRANSPORT THAT CAN LEAD TO AN OVERALL INCREASE OF METABOLIC RATE IN ANIMALS

Question 24

endocytosis

Answer 24

How Larger toxicants enter

Cell membrane forms vesicle and carries hydrophilic compounds across cell membrane

Question 25

receptor-mediated endocytosis,

Answer 25

cells have receptors that recognize certain proteins and form a vesicle, which contains the protein

Question 26

Main sites of absorption are:

Answer 26

1. Gastrointestinal (GI) tract
2. Lungs
3. Skin

Question 27

Enteral administration

Answer 27

includes all routes involving the alimentary canal • i.e., Sublingual, oral, rectal

Question 28

Parental administration

Answer 28

includes all other routes

• i.e., Injection

Question 29

What is the major absorption site for toxicants?

Answer 29

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.

Question 30

How do gases and vapors get absorbed?

Answer 30

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

Question 31

Aerosols

Answer 31

Deposition where they end up in body) of aerosols depends on the size.(same thing with particulate matter)

small droplet of liquid

Question 32

GASES AND VAPOR GETS ABSROBED RLY EASILY AND AERSOL AND PARTICULATES DEPEND ON SIZE
TRUE OR FALSE

Answer 32

TRUE

Question 33

Particulate

Answer 33

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

Question 34

Toxicant absorption through the skin

Answer 34

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.

Question 35

hydrated stratum corneum

Answer 35

is the rate-determining barrier of skin. Thicker on palms and soles than on arms, back, legs, etc.

Question 36

Toxicant storage through the body

Answer 36

Different toxicants can be stored at different sites in the body depending on their properties. Storage sites aren’t always the target of toxicity!

Question 37

Blood

Answer 37

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).

Question 38

Liver and Kidney

Answer 38

• Involved in the metabolism and excretion of toxicants, but can also be a site of storage.

Question 39

Fat

Answer 39

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

Question 40

Blood brain barrier

Answer 40

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!

Question 41

What can pass thru the blood brain barrier?

Answer 41

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.