1. 1 Some Deterministic Models in Mathematical Biology: Physiologically Based Pharmacokinetic Models for Toxic Chemicals Cammey E. Cole Meredith College January 7, 2007

2. 2 Outline Introduction to compartment models Research examples Linear model –Analytics –Graphics Nonlinear model Exploration

3. 3 Physiologically Based Pharmacokinetic (PBPK) Models in Toxicology Research A physiologically based pharmacokinetic (PBPK) model for the uptake and elimination of a chemical in rodents is developed to relate the amount of IV and orally administered chemical to the tissue doses of the chemical and its metabolite.

4. 4 Characteristics of PBPK Models Compartments are to represent the amount or concentration of the chemical in a particular tissue. Model incorporates known tissue volumes and blood flow rates; this allows us to use the same model across multiple species. Similar tissues are grouped together. Compartments are assumed to be well-mixed.

5. 5 Example of Compartment in PBPK Model Q K is the blood flow into the kidney. CV K is the concentration of chemical in the venous blood leaving the kidney. QKQK CV K Kidney

6. 6 Example of Compartment in PBPK Model C K is the concentration of chemical in the kidney at time t. C Bl is the concentration of chemical in the blood at time t. CV K is the concentration of chemical in the venous blood leaving the kidney at time t. Q K is the blood flow into the kidney. V K is the volume of the kidney.

7. 7 Benzene Aveloar Space Lung Blood Fat Slowly Perfused Rapidly Perfused Liver Stomach Muconic Acid ExhaledInhaled Venous Blood CV Arterial Blood CA Slowly Perfused Blood Liver Blood Liver Blood Liver BO PH HQ BZ Conjugates PH Catechol THB Conjugates HQ PMA Benzene Benzene OxidePhenolHydroquinone Rapidly Perfused Fat BOPH Slowly Perfused PH Fat PH Rapidly Perfused Fat Slowly Perfused Rapidly Perfused HQ

8. 8 Benzene Plot

9. 9

10. 10 4-Methylimidazole (4-MI) Other Tissues Adipose Kidney Urine Liver BloodBlood Initial condition: IV exposure Stomach Initial condition: gavage exposure Feces Metabolite

11. 11 4-MI Female Rat Data (NTP TK)

12. 12 4-MI Female Rat Data (Chronic)

13. 13 Linear Model Example A drug or chemical enters the body via the stomach. Where does it go? Assume we can think about the body as three compartments: –Stomach (where drug enters) –Liver (where drug is metabolized) –All other tissues Assume that once the drug leaves the stomach, it can not return to the stomach.

14. 14 Schematic of Linear Model x 1, x 2, and x 3 represent amounts of the drug in the compartments. a, b, and c represent linear flow rate constants. Stomach Other Tissues Liver x2x2 x1x1 x3x3 a bc

15. 15 Linear Model Equations Let’s look at the change of amounts in each compartment, assuming the mass balance principle is applied.

16. 16 Linear Model Equations Let’s look at the change of amounts in each compartment, assuming the mass balance principle is applied.

17. 17 Linear Model (continued) Let’s now write the system in matrix form.

18. 18 Linear Model (continued) Find the eigenvectors and eigenvalues. Write general solution of the differential equation. Use initial conditions of the system to determine particular solution.

19. 19 Finding Eigenvalues

20. 20 Finding Eigenvectors Consider

21. 21 Finding Eigenvectors

22. 22 Finding Eigenvectors Consider

23. 23 Finding Eigenvectors

24. 24 Finding Eigenvectors Consider

25. 25 Finding Eigenvectors

26. 26 Linear Model (continued) Then, our general solution would be given by:

27. 27 Parameter Values and Initial Conditions For our example, let a=3, b=4, and c=1, and use the initial conditions of we are representing the fact that the drug began in the stomach and there were no background levels of the drug in the system.

28. 28 Linear Model (continued) Then, our particular solution would be given by: with

29. 29 Graphical Results Link1 Link2 Link1 Link2

30. 30 Schematic of Nonlinear Model x 1, x 2, x 3, and x 4 represent amounts of the drug (or its metabolite). Liver x2x2 Stomach x1x1 a Other Tissues x3x3 bc Metabolite x4x4

31. 31 Nonlinear Model Equations

32. 32 Nonlinear Model Link 1 Link2 a=0.2, b=0.4, c=0.1, V=0.3, K=4 Link 1Link2

33. 33 Exploration What would happen if the parameter values were changed? What would happen if the initial conditions were changed? We will now use Phaser to explore these questions.