Toxicokinetic Modeling

Question 1

What is the definition of Toxicokinetics?

Answer 1

The mathematical description of the time course of disposition (ADME) of xenobiotics in the body

Question 2

What are the 3 key concepts of toxicokinetics?

Answer 2

• Bioavailability (F)
  *Fraction of it that gets
• Volume of distribution (Vd)
• Clearance (CL; overall efficiency of xenobiotic removal from body)
  *CL= 100mL/min means 100mL of blood is cleared of that xenobiotic every minute.

Question 3

Very lipophilic xenobiotics follow what simple model?

Answer 3

The one-compartment model
One-Compartment Model
|
| Ka
| Kel
1. Body of an animal ——————>

*legacy contaminents

Question 4

What is the math for the one-compartment model?

Answer 4

Cp= Co e^-Kel*t
Cp = blood plasma concentration
C0 is Cp at time zero
Kel = the elimination rate constant, determined from the slope of Log Cp vs. Time graph
exponential down curve

Question 5

Clearance CL = ?

Answer 5

CL = Vd x Kel

Question 6

Most xenobiotics (including drugs) follow what type of model?

Answer 6

A two-compartment model

Two-compartment Model
|
| Ka
| K12
1. Central <————>2. Peripheral
| K21
| K10
|

K12 & 21 being the concentration gradient
Central being the highest concentration in blood stream (circulation)

Question 7

What is the math for the Two-compartment model?

Answer 7

Cp = Ae^(-alpha t) + Be ^(beta t)
- A and B are y-intercepts
- alpha is slope of distribution phase
- Beta is slope of elimination phase
- Beta is the elimination rate constant, also known as Kel in the one compartment model

Question 8

What is PBPK model

Answer 8

Physiologically-Based Pharmaco/toxicokinetic

Qt x Cin ——> Vascular Space Flux 1 —–> QtxCout
^|
Interstitial Space. Flux 2
^
|
Intracellular Space
Binding Sites

Question 9

First order kinetics

Answer 9

Elimination is proportional to Cp (plasma concentration)
the graph is a curved line, higher to the left and decreases as it goes to the right

Question 10

Zero Order kinetics

Answer 10

Elimination is independent of Cp
(constant elimination)
Cp vs Time - not one compartment model
the graph is a straight line, higher to the left and decreases as it goes to the right

Question 11

Steady State

Answer 11

attained after approximately four half-times
time to steady state independent of dosage

demonstrated ADME exposed to multiple doses

Question 12

Steady State concentrations

Answer 12

proportional to dose/dosage interval
proportional to F/CL

Question 13

Fluctuations

Answer 13

proportional to dosage interval/half-time
blunted by slow absorption

Question 14

In certain cases PBPK models are used for drugs and toxicants that….

Answer 14

exhibit “unusual” toxicokinetics and/or are dangerous drugs with a narrow therapeutic window

Question 15

xenobiotics exhibiting zero order toxicokinetics are dangerous why?

Answer 15

because elimination is constant, thus at higher doses the risk of toxicity is significant
difference between dose that will kill you , and dose that gets rid of your headache

Question 16

How do xenobiotics exhibit first order kinetics at lower doses and the ‘switch’ to zero order kinetics at higher doses?

Answer 16

due mainly to saturation of biotransformation enzymes
higher substrate

Question 17

Bioaccumulation=
commonly occurs with….

Answer 17

the net accumulation of a xenobiotic in an organism from all exposure routes (eg. food, water, air, soil)
… highly lipophilic contaminants (ie. log Kow> 4) and dietary exposure
fatty foods

Question 18

Biocincentration

Answer 18

specific case where net accumulation of xenobiotic in an organism is from water only, through respiratory surfaces or skin (e.g fishes, crustaceans, molluscs)

Question 19

with what does bioconcentration most commonly occur

Answer 19

with metals and certain organic chemicals in aquatic ecosystems

Question 20

what is BCF

Answer 20

Bioconcentration Factor
BCF = [xenobiotic in organism]/[xenobiotic in water]

Question 21

Bioaccumulation and bioconcentration only occur when..

Answer 21

the rate of xenobiotic absorption exceeds the rate of xenobiotic excretion

Question 22

Biomagnification

Answer 22

Occurs when xenobiotic concentration increase through at least three trophic levels in a food chain
- definitions vary, but generally at least a 10-fold increase in each step in the food chain

Question 23

when does biomagnification usually occurs?

Answer 23

usually only occurs with xenobiotics 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