Chapter 3 (exam 2) Flashcards
Toxico/pharmoco-dynamics
time course of the effect
-biokinetics/biodynamic
Toxicokinetics
- time course for absorption, distribution, metabolism, and excretion
- all relates to the concentration at the target site
Noncompartmental analysis
- kinetic model
- single dose analysis used in initial phase of pharm testing
Classical compartmental models
- kinetic model
- consider multiple does in simplified system of compartments
Physiologically based pharmokinetics
- kinetic model
- tissue and organ specific most realistic most complicated
Compartment
- not a specific organ or tissue
- empirical model for lab data
- in-out = storage (mas balance)
- based on blood plasma conc and conc in tussues are assumed to be proportional
- tissues that behave differently (depots) are an additional compartment
Reversible vs irreversible compartment
Reversible - X+R equilibrium XR
Not true for a covalent process
First Order Kinetics
- rate dependant on the concentration
- probablility of reaction decreases as [X] decreases
- most common type in pharmaco/toxicoknietics
Zero order kinetics
constant rate over time
dC/dt = -k
C=Co-kt
Negative linear line
saturated enzyme or transporter
Second Order Kinetics
rate depends on concentration of more than one component
dC/dt = -k[Ca][Cb]
Collapses to pseudo first order when one concentration is high enough to be about constant (ex. GSH normally high enough to not change as compound is metabilized. Follows second order when severely depleted)
dC/dt = -k’ [A]
Saturable (capacity limited kinetics)
- also known as Michaelis-Menton
- at low concentrations, transporters (or metabolic enzymes) are available for additional substrate molecules to interact with
–increase saturation conc increases rate
-high conc all sites are occupied
–increase substrate does not increase rate
Michaelis-Menton Kinetics
Probablility of randomly interacting with the enzyme increases with conc but saturated and rate can not increase further
- below saturation, increase conc increase probability of binding
- saturated, probability is constant and binding will not increase with increase conc
Compartment Models
- open model - IV injection no uptake step
- open model w/first order absorption
- 2 compartment open model - IV injection, no uptake, 2 different kinetic areas
- 2 compartment open model with first order absorption
- Ka=kinetics of absorption (first part of graph)
- Ke=kinetics of excretion (second part of graph)
Model fitting
C = ae-kt+Be-k2t
R2 used to determine best fit
Empirical process
Physicologically based pharmokinetics model (PBPK)
- measure flow rates, partition coefficient for each compartment
- expensive
- lots of data
- could be very powerful for important toxicants
Chemical Effects on Enzymes
- enzyme induction
- enzyme inhibition
–competitive
–uncompetitive
–noncompetitive
Reversible inhibitor-affinity of I may not be equal to the affinity of S
S+E equil E+S Kf
I+E equil E+I KI
Competitive inhibition
-inhibitor and substrate compete for binding site on the enzyme
Classical-compete for same site
Nonclassical-compete for different sites that cause confirmation change(allosteric effect) and other cannot bind
Uncompetitive Inhibition
inhibitor binds after the substrate and to a different site, then inhibits the enzyme
-not dependent on substrate conc
