4. absorption and toxicokinetics

Question 1

flu vaccines

Answer 1

We develop flu vaccines to match the known strains of influenza virus each year expected to be a problem.

Question 2

disposition of a toxicant

Answer 2

Absorption, Distribution, Biotransformation, Elimination

-depends on the properties and dose of toxicant

Question 3

Absorption

Answer 3

is the process of toxicants moving across cell body membranes and into the bloodstream or lymph system.

Question 4

local

Answer 4

in a specific tissue

Question 5

systemic

Answer 5

throughout the organism

Question 6

Cell types are often:

Answer 6

• 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

Question 7

Cell membranes are:

Answer 7

• Lipid bilayers made mostly of
phospholipids
• Full of proteins (integral membrane
proteins, peripheral proteins, etc.) • Coated in carbohydrates on the
exterior of the cell

Question 8

Toxicants mostly diffuse through ____ before entering the _______.

Answer 8

tissues, bloodstream

Question 9

Diffusion

Answer 9

net movement of molecules from an area of high concentration to low concentration

Question 10

Transcellular diffusion

Answer 10

diffusion of toxicants through cells (therefore must pass through cellular membranes). This occurs if the cells are packed tightly with little space between them

Question 11

Paracellular diffusion:

Answer 11

diffusion of toxicants in-between cells.

-via tight junctions

Question 12

Passive transport

Answer 12

Diffusion, Filtration

Question 13

Passive transport • Diffusion

Answer 13

• 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

Question 14

Most toxicants are somewhat large and vary in how lipophilic they are

Answer 14

Their rate of transport correlates with their lipid solubility

Question 15

Filtration

Answer 15

• 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

Question 16

“Special” transport

Answer 16

Active transport, Facilitated diffusion, Xenobiotic (and other things…) transporters

Question 17

Active transport

Answer 17

• 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..

Question 18

Facilitated diffusion

Answer 18

Carrier mediated transport that does not require energy

Question 19

Xenobiotic (and other things…) transporters

Answer 19

2 categories:
• ATP-binding cassette (ABC) transporters
• Largelyfunctionthroughactivetransport • Solutecarriers
• Largelyfunctionthroughfacilitativediffusion

Question 20

endocytosis

Answer 20

-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).

Question 21

receptor-mediated endocytosis,

Answer 21

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.

Question 22

Main sites of absorption are:

Answer 22

• Gastrointestinal (GI) tract
• Lungs – usually gases, vapors of volatiles and aerosols
• Skin

Question 23

Enteral administration

Answer 23

includes all routes involving the alimentary canal

• i.e., Sublingual, oral, rectal

Question 24

Parental administration

Answer 24

includes all other routes • i.e., Injection

Question 25

The Gastrointestinal (GI) tract is a major absorption site for environmental toxicants that enter the food chain

Answer 25

• 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.

Question 26

The major areas of the human gastrointestinal tract

Answer 26

liver, stomach, large intestine, small intestine

Question 27

liver

Answer 27

• 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

Question 28

stomach

Answer 28

``` • pH = 2 • May degrade toxicants (esp. proteins) • Low pH will help in the absorption of weak acids (e.g., the NSAID naproxen) ```

Question 29

small intestine

Answer 29

• pH 6 to 7.5 • major area of nutrient uptake

Question 30

large intestine

Answer 30

• pH 6 • major area of water uptake • Natural gut bacteria can convert toxicants to different forms

Question 31

Multidrug-resistant (MDR) and multiresistant drug (MRP) proteins

Answer 31

move xenobiotics out of cells.

Question 32

The lungs are a major site of absorption fo

Answer 32

gases, vapors of volatile liquids and aerosols.

Question 33

Gases and Vapors

Answer 33

• 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.

Question 34

Aerosols

Answer 34

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

Question 35

Gasses and vapors can be inhaled and readily pass into the bloodstream.

Answer 35

Each gas/vapor has it’s own properties | that indicate how quickly equilibrium is reached

Question 36

Aerosols and Particulates | Aerosol = small droplet of liquid Particulate = small chunk of solid matter

Answer 36

• 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

Question 37

• Toxicant absorption through the skin

Answer 37

• 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.

Question 38

Absorption through the skin can increase by:

Answer 38

- Damage to the stratum corneum - Increased hydration - Increased blood flow - Size of toxicant (small ones increase absorption)

Question 39

Toxicant storage through the body

Answer 39

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!

Question 40

toxicant storage: Blood

Answer 40

• 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)

Question 41

toxicant storage: liver and kidney

Answer 41

Involved in the metabolism and excretion of toxicants (more on this later), but can also be a site of storage

Question 42

toxicant storage: fat

Answer 42

Most organic toxicants are hydrophobic, so will accumulate in adipose tissue • But can be released later

Question 43

dieldrin poisoning.

Answer 43

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.

Question 44

blood brain barrier

Answer 44

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

Question 45

Toxicokinetic modelling

Answer 45

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?

Question 46

“Classic”toxicokinetics

Answer 46

assume the compounds move through the body as if there were only 1 or 2 compartments.

Question 47

• One-compartment model

Answer 47

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.

Question 48

Two-compartment models

Answer 48

``` 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 ```

Question 49

Physiologically based toxicokinetic models

Answer 49

represent a series of mass balance equations that describe each tissue.