Disposition of Toxicants Flashcards
disposition is defined as four things
absorption
distribution
metabolism
excretion
the toxicity of a substance is directly dependent on the
dose
the amount of a chemical that ultimately reaches the site or sites of action
dose
major organs through with absorption takes place
GI tract
Lungs
Skin
first barrier toxicants meet
cell membranes
two characteristics of phospholipid bilayer
polar heads, lipid tails
saturation determines fluidity
types of proteins associated with the cell membrane
receptors, transporters, pore formers
outer coatings associated with the cell membrane
glycoproteins
glycolipids
two types of membrane transport
passive transport
active transport
two types of transport included in passive transport
simple diffusion
filtration
most toxicants cross the membrane by simple diffusion following the principles of
fick’s law
ficks law establishes….
chemicals move from regions of higher concentration to regions of lower concentration
two characteristics of simple diffusion
small hydrophilic molecules through aqueous pores
hydrophobic molecules through phospholipid bilayer
how well compound dissolves in hydrophobic environment
Kow
the charge of the molecule is told by this
pKa
what compound is commonly used to find Kow
octanol
driven by hydostatic pressure or osmotic pressure
filtration
driven by concentration gradient
diffusion
active transport is characterized by 5 things
- movement against electrochemical or concentration gradient
- saturability at high substrate concentrations
- selectivity among chemicals
- competitive inhibition
- requirement for expenditure of energy
applies to carrier mediated transport that exhibits the properties of active transport except that the substance is not moved against an electrochemical or concentration gradient and no energy is required
facilitated diffusion
when diffusion does not work…
compounds are too large for pores
compounds are too hydrophilic for diffusion
transport against a concentration gradient
functions as an efflux pump which in cancerous cells exudes cytotoxic drugs out of the tumor cells and contributes to their resistance
P-glycoprotein or MDR-1 family
excrete chemicals from cells
MRP family
important in the efflux of xenobiotic metabolites, especially those conjugated with UDP-glucuronic acid or glutathione
MRP 2 and 3
xenobiotic transporters which function predominately as facilitative transporters
SLC family (solute carriers)
important membrane transporters that mediate the sodium independent transport of a wide range of compounds, including organic acids, bases, and neutral compounds
OATP family (organic anion transporting peptides)
process by which toxicants cross body membranes to enter the bloodstream
absorption
first place most toxicants are absorbed from
GI tract
most common places along the GI tract for absoption
stomach, intestine, rectum
if a toxicant is an organic acid or base it tends to be absorbed where
by simple diffusion in the part of GI tract where it exists in the most lipid soluble form
where does iron accumulate in the GI tract
mucosal cells
in what form is iron in the GI tract
ferritin
what does calcium need for absorption
vitamin D
particles and particulate matter can also be absorbed by the GI tract but this matters more than this
size more than lipid solubility
enter intestinal cells by pinocytosis
large particles
5-flurorouracile hitchhikes with
pyrimidine
Thallium, cobalt, manganese hitchhike with
iron
lead hitchhikes with
calcium
some antibiotics hitchhike with
dipeptides
five additional factors affecting absorption in GI tract
pH presence of food digestive enzymes bile acids bacterial microflora in the GI tract
three differences between species when it comes to GI absorption
thickness of unstirred layer
length and surface area of GI tract
microflora differences
infants are more susceptible to this because the higher pH in the neonatal GI tract is permissive for the growth of bacteria
methemoglobinemia
major anatomical layer that controls absorption across the skin
stranum corneum
dermal areas where absorption may occur
sweat glands
hair follicles
all toxicant move across the stratum corneum by
passive diffusion
what absorbs more readily across the stratum corneum
lipophilic compounds
where to lipophilic compounds have trouble diffusing through
the dermis
six factors that influence the absorption of toxicants
thickness hydration status damages such as leakes vascularization influence of solvents species differences
acids and alkalis can ___permeability
increase
more hydration ____ permeability
increases
increase in temperature ____permeability
increases
____absorption if a toxicant is highly soluble in a vehicle
lower
compounds above ___exhibit poor dermal penetration
400 Da
