Absorption and Toxicokinetics Flashcards
Functional antagonism
2 toxicants produce opposite effects on a physiological function
chemical antagonism
chemical reaction between the compounds leads to an inactivation that produces a less toxic effect
dispositional antagonism
alters the absorption, biotransformation, distribution or elimination of the toxicants
receptor antagonist
2 toxicants bind to the same receptor and interfere with the response
disposition
- composite of its absorption, distribution, biotransformation, elimination
- depend on the properties of the toxicant
- depends on the dose
absorption
- when toxicants cross cell membranes and enter the bloodstream or lymph system
- effects may be local or systemic
Toxicants to targets
- pass through many cell types and membranes to reach their targets
- exchange of gases and other materials occurs in blood capillaries located below the basement membrane
cell types are often
- stratified epithelium (skin)
- thin cell layers of epithelium of the lungs and gastrointestinal tract
cell membranes
- semipermeable
- phospholipid bilayer
- transmembrane proteins
- lipophilic compounds diffuse through the lipid layer
- proteins can form pores and transporters to move other larger compounds or hydrophilic compounds
passive transport
- diffusion
- filtration
diffusion
- net movement of molecules from an area of high concentration to low concentration
- small hydrophobic toxicants move through aqueous pores
- small hydrophobic diffuse across membranes correlates with their lipid solubility
transcellular diffusion
- diffusion of toxicants through cells, passing through cell membranes
- occurs if the cells are packed tightly with little space between them
paracellular diffusion
diffusion of toxicants in-between cells
filtration
- water flows across a porous membrane, small molecules can move with it
- important in renal glomeruli in the kidneys
carrier mediated transport
- active transport
- facilitated diffusion
- xenobiotic transporters
active transport
- movement against gradients
- saturated
- competitive inhibition
facilitated diffusion
carrier mediated transport that does not require energy
xenobiotic transporters
- ATP-binding cassette (ABC) transporters=largely function through active transport
- Solute carriers=largely function through facilitative diffusion
endocytosis
- larger toxicants can enter cells
- large molecules
receptor-mediated endocytosis
-cells have receptors that recognize these proteins and pinch off some of the cell membrane to form a vesicle that contains proteins
protein toxins
-heterodimers made of the toxin and multiple beta subunits
beta subunits
-binds to membrane components and tricks the cell into taking in the toxin
main sites of absorption
- gastrointestinal tract
- lungs
- skin
enteral administration
- all routes involving the alimentary canal
- sublingual, oral, rectal
parental administration
-injection
GI
- absorbs nutrients from gut into the bloodstream
- absorbed via diffusion
- many transporters and electrolytes used to move xenobiotics from the intestine to the bloodstream
- rate of absorbance of a toxicant increases the longer it stays in the intestine
liver
- chemicals first go through the livers via the hepatic portal
- major site of metabolism
- target organ for many toxicants
- can extract toxicants and excrete them into bile
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
stomach
- ph 2
- may degrade toxicants
- low ph will help the absorption of weak acids
MDR and MRP
- multidrug-resistant
- multi-resistant drug proteins
- move xenobiotics out of cells
gases and vapours
- gas molecules diffuse from the alveoli space into the blood until at equilibrium
- blood distributes the gases throughout the body and where they can be transferred to target tissues
- blood pick up more gas at the lungs
- keep happening until the gas is in equilibrium in the lungs, blood and target tissue
aerosols
- deposition of aerosols depends on the size
- greater then 5 micro meters=nasopharyngeal region
- 2.5 micro meters=lungs
- less then 1 micro meter=alveolar sacs, potentially enter the blood
aerosol definition
-small droplet of liquid
particulate
- small chunk of solid matter
- swept out by cilia
- some particles hang around for months to years
skin absorption
- minor route
- passively diffuse through the stratum corneum, rate determining barrier
- must pass through several cell layers 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
toxicant storage through the body
- bound in different storage sites in the body
- aren’t always the target of the toxicant
- blood, liver and kidney, fat
blood
- albumin protein in the blood, can bind toxicants
- transport fat, hormones, and hydrophobic compounds
- reversible process
live and kidney
- metabolism and excretion of toxicants
- site of storage
fat
- organic toxicants are hydrophobic, so accumulate in the adipose tissue
- release from fat deposits can be a significant source of toxicants in the blood
blood brain barrier keeps many toxicants out of the brain because..
- capillaries in the brain have few pores, limiting diffusion
- capillary endothelial cells have MDR transporters that can pump unwanted chemicals back into the bloodstream
- paracellular transport limited
- evolved to keep natural toxins out of our brains
- hydrophobic non-ionic chemicals can readily pass through
- poorly developed in infants
toxicokinetics
- compound move through the body as if there were only 1 or 2 compartments
- represent a series of mass balance equations that describe each tissue
one compartment model
-linear relationship when the log plasma concentration is plotted over time
two compartment model
- central tissues and peripheral tissues
- curved line when the log plasma concentration is plotted over time
