1 toxicokinetic modeling Flashcards
what is the definition of toxicokinetic modeling?
the mathematical description of the time course of disposition (ADME) of xenobiotics in the body
-the basic hypothesis is that a relationship exists between the toxicological effect of a xenobiotic and the concentration of that xenobiotic in the systemic circulation
what are the three key concepts on toxicokinetic modeling?
-bioavailability (F)
-volume of distribution (VD)
-clearance (CL; overall efficiency of xenobiotic removal from body) (ex: CL=mL/min means 100mL of blood is cleared of that xenobiotic every minute)
what is the one-compartment model?
very lipophilic xenobiotics follow a simple one-compartment model (with Kow value greater than 4)
-there is a rate of absorption and a rate of elimination from the body and the body just acts as a single homogenous compartment (like a bag of water)
what is the math of the one-compartment model?
when graph has a straight line, it means the one-compartment model
what is the two-compartment model?
most xenobiotics (including drugs) follow a two-compartment model
-peripheral is just everything outside the systemic circulation
what is the math of the two-compartment model?
what are PBPK models?
physiologically-based pharmaco/toxicokinetic models
-break down the peripheral compartment into many different compartments (like into each organ system)
-Q is flow rate
-very expensive and hard to test
what are the kinetics of elimination?
-ethanol follows zero order kinetics (why breathalyzer is so effective)
what is the steady state?
repeated dosing (oral)
-equilibrium concentrations
what do most xenos follow?
a two compartment model and first-order toxicokinetics
-xenos that follow one comp model are highly lipophilic
why is zero order bad?
xenos exhibiting first order toxicokinetics are dangerous because elimination is constant, thus at high doses the risk of toxicity is significant
-a xeno can exhibit first order at lower doses and then “switch” to zero order kinetics at higher doses, due mainly to saturation of biotransformation enzymes
what happens in certain cases of PBPK models?
-PBPK models are used for drugs and toxicants that exhibit “usual” toxicokinetics and/or are dangerous drugs with a narrow therapeutic window
what is bioaccumulation?
the net accumulation of a xeno in an organism from all exposure routes (ex: food, water, air, soil)
-commonly occurs in highly lipophilic contaminants (eg: log Kow>4) and dietary exposure
what is bioconcentration?
specific case where net accumulation of a xenobiotic in an organism is from water only, through respiratory surfaces or skin (ex: fishes, crustaceans, molluscs)
-most commonly occurs with metals and certain organic chemicals in aquatic ecosystems
-bioconcentration factor (BCF)
-BCF=[xenobiotic in organism]/[xenobiotic in water]
when do bioaccumulation and bioconcentration occur?
only occur when the rate of xenobiotic absorption exceeds the rate of xenobiotic excretion
what is biomagnification?
occurs when xeno conc increase through at least three tropic levels in a food chain
-definitions vary, but generally at least a 10-fold increase in each step in the food chain
-usually only occurs with xenos with very high lipophilicity (log Kow>5)
-persistent organic pollutants (POPs) or legacy contaminants: concentration in top predators can be >1,000,000 times greater than concentration in water
