1. Dosimetry and Kinetics
Oct
Casarett and Doull, Chapter 7, pp
Timbrell, Chapter 3, pp 48-61

3. Exposure External exposure – ambient air, water Dose received by body
Dose at target organ
Dose at target tissue
Dose at target molecule

4. Exposure – Dose How are they related. Can we measure them
Exposure – Dose How are they related ? Can we measure them ? How can we describe the crucial steps so that we can estimate what we can’t measure?

5. The single compartment (one compartment) model
kin
kout

6. Kinetics of absorption
Absorption is generally a first-order process
Absorption constant = ka
Concentration inside the compartment = C
C/t = ka * D where D = external dose

7. First-Order Processes
Follow exponential time course
Rate is concentration-dependent
v = [A]/t = k[A]
Units of k are 1/time, e.g. h-1
Unsaturated carrier-mediated processes
Unsaturated enzyme-mediated processes

8. Kinetics of elimination
Elimination is also generally a first-order process
Removal rate constant k, the sum of all removal processes
C/t = -kC where C = concentration inside compartment
C = C0e-kt
Log10C = Log10C0 - kt/2.303

9. Kinetics of Enzyme-catalyzed Reactions
Michaelis-Menten Equation:
v = Vmax * [S]
Km + [S]
First-order where Km >> [S]
Zero-order where [S] >> Km

10. Second-Order Processes
Follow exponential time course
Rate is dependent on concentration of two reactants
v = [A]/t = k[A]*[B]

11. First-order elimination
Half-life, t1/2
Units: time
t1/2 = 0.693/k

12. One compartment system

13. First-order decay of plasma concentration

14. Total body burden Integration of internal concentration over time
Area under the curve

15. Area under the curve (AUC)

16. A more complex time-course

17. The two-compartment model
Tissues
Central
compartment
Peripheral
kin
kout
Plasma

18. The three-compartment model
Deep
depot
Peripheral
compartment
kin
kout
Central
Slow equilibrium
Rapid equilibrium

19. The four-compartment model
Mamillary model
Peripheral
compartment
kin
Central
compartment
Deep
depot
Kidney
kout

20. The four-compartment model
Catenary model A B C D
kout
kin

21. Physiologically-Based Pharmacokinetic Modeling
Each relevant organ or tissue is a compartment
Material flows into compartment, partitionnns into and distributes around compartment, flows out of compartment – usually in blood
If blood flow rates, volume of compartment and partition coefficient are known, can write an equation for each compartment
Assuming conservation of mass, solve equations simultaneously – can calculate concentration (mass) in each compartment at any time

22. Example of equation δkidney/δt = (Cak * Qa) – (Ck * Qvk) IN OUT
Rate of change of the amount in the kidney =
Concentration in (incoming) arterial blood X arterial blood flow
Minus
Concentration in (outgoing) venous blood X venous blood flow

23. Example of a model Air inhaled Lungs Venous blood Arterial blood
Rest of body
Liver
Metabolism
Kidneys
Urine