Toxicokinetics Flashcards
Toxicity
a measure of the degree to which something is toxic or poisonous
Xenobiotic
Compound with a chemical structure foreign to a given organism
Factors affecting response to toxic chemical
he substance
* Dose (dose-response)
* Uptake into the body (absorption)
* Movement within the body (distribution)
* [Accumulation]
* Chemical conversion to non-toxic or toxic substance (metabolism) * Removal from the body (excretion)
One-compartmental model
Xenobiotic distributes into a single, homogenous “vessel”
n- compartment model
Xenobiotic distributes into a central, and then to one ore more peripheral compartments.
Thermodynamic
Involves the relationship between total concentration of xenobiotic in tissue and the free concentration within the tissue
* Assumes equilibrium between total and free xenobiotic
* Only free is available for binding, metabolism or removal from the
tissue by blood
* Need to know partition or distribution coefficients for calculations
First-pass metabolism
Process of biotransformation of xenobiotic before reaching systemic circulation
Small intestine and liver
Bioavailability
The actual extent of exposure as defined by the amount of toxicant reaching the systemic circulation is determined by (1) entry barrier permeability, and (2) the extent of “first-pass” metabolism
* The fraction of dose reaching the system circulation in intact form, or systemic availability (F), is estimated from the AUCs,
Vd
Apparent volume of distribution
ke
Total elimination rate constant
Apparent volume of distribution(Vd)
space in which an amount of chemical is distributed in the body to result in a given plasma concentration
Total amount of drug in the body/drug blood plasma concentration
X/c
Total elimination rate constant, k [h-1]
The fraction of xenobiotic eliminated per unit time
Elimination from: Metabolism
Km
Elimination from: Kidneys
kr
Elimination from: Lungs
kx
ke =
km + kr +kx
Elimination rate, -dX/dt [mg h-1]
the rate at which xenobiotics are removed from the system
X
amount of xenobiotic
First order elimination
Amount of xenobiotic eliminated is proportional to the concentration of xenobiotic in plasma
- dC/dt = k * c e
c
concentration of xenobiotic
What is the concentration of a xenobiotic at a given time..?
ct = co * e^-ke*t
co
initial concentration (at time 0)
ln Ct =
- ke * t + ln C0
ke =
ln C0 - ln Ct / t – t0
Half life, t1/2
The half-life of elimination t1/2 is the time required for the blood or plasma xenobiotic concentration to decrease by one-half (and is dependent on both volume of distribution and clearance)…
t1/2 =
ln2 / ke = 0.693 / ke
First order kinetics
For first order elimination, the rate at which a chemical is eliminated at any time is directly proportional to the amount of that chemical in the body at that time
Concentration of chemical in plasma and other tissues decreases similarly by some constant fraction per unit of time, the elimination rate constant, ke
One – compartment model
first order kinetics
xenobiotic distributes into a single, homogenous “vessel”
Zero order elimination
- dC/dt = constant
Rate or amount of chemical eliminated at any time is independent of the amount of chemical in the body
For zero order processes, the arithmetic plot of plasma conc. vs time yields a straight line
A true t1/2 or ke does not exist but differs depending on the dose
