1. MS Phoenix WinNonLin Project
Due 9/21/15
Non-compartment analysis (NCA) of simulated oral plasma data
Everyone uses drug.
Plot and Table

2. Integration of Kinetic and Physiological Concepts
Lecture #12
Integration  of  Kinetic  and  Physiological   Concepts

3. Clearance vs. V vs. t1/2 Increase V; Increase CL
Decrease t1/2; Increase CL

4. k, t1/2 and AUC Unspoken Assumption: First Order Exponential Decay
Kinetics

5. Future Current: Kinetics IV bolus dose We will
Kinetics Extravascular Dose
Constant-Rate Input
Multiple-Doses
Disease
Non-linearities
Drug Interactions

6. PK Parameters vs. Physiological Variables
Primary PK Parameters
Protein binding, enzyme activity, blood flows and partitioning
Dose, V, CL, CLH, CLR, CLINT, dose, fu, blood-to-plasma equilibration ratio, Q, QR, QH
Secondary PK Parameters
Depend on Primary PK parameters
Drug Concentrations, Rate Constants, AUC
k = CL/V
Observations
AUC = Adose/CL
CMAX = Adose/V
Cu = fu (Adose/V)

7. Hepatic Extraction Ratio (EH)
High EH
Clearance cannot exceed
hepatic blood flow (QH)
Low EH

8. Hepatic Extraction Ratio (Eh)
Enzymatic Activity/Concentration (CLint)
Hepatic Blood Flow (Qh)
Protein Binding (fu)

9. Low EH (Sensitive to Enzyme Activity)
Inhibitor
opioid analgesic drug
Inducer
Rifpampin
(Antibiotic)
Troleandomycin (macrolide antibiotic)
Cytochrome P450 3A4

10. Low EH (Sensitive to Enzyme Activity)
Inhibited
CLint =1 L/hr
fu = 1
Hepatic
Clearance
(CLH)
Induced
Hepatic
Extraction
Ratio
(EH)

11. Low EH (Insensitive to hepatic blood flow (QH))
CLint =1 L/hr
fu = 1
Hepatic
Clearance
(CLH)
Hepatic
Extraction
Ratio
(EH)

12. low EH (Sensitive to Protein Binding)
CLint =1 L/hr
Hepatic
Clearance
(CLH)
Hepatic
Extraction
Ratio
(EH)

13. low EH (Sensitive to k and t1/2)
CLint =1 L/hr
Elim.
Rate
Constant
(k)
Half time (t1/2)

14. high EH (Insensitive to Enzyme Activity)
Heart Drug
P450 Inducer
Pentobarbital is a sedative.
Pentobarbital
Inhibitors?
Cytochrome P450 (P450)

15. high EH (Insensitive to Enzyme Activity)
Low Inhibition
Recall:
P450
Inhibitor
P450
Inhibitor
Cytochrome P450 3A4 inhibitor
P450 = Cytochrome P450
synthetic opioid analgesic

16. high EH (Insensitive to Enzyme Activity)
High Inhibition
P450 inhibitor
P450 = Cytochrome P450
synthetic opioid analgesic

17. High EH (Insensitive to Enzyme Activity)
Induced
Inhibited
CLint =1000 L/hr
fu = 1
Hepatic
Clearance
(CLH)
Hepatic
Extraction
Ratio
(EH)
Induced
Inhibited

18. high EH (Sensitive to Blood Flow)
Reduce QH
Local Anesthetic
Anti-hypertensive
Anti-hypertensive

19. high EH (Sensitive to Blood Flow)
CLint =1000 L/hr
fu = 1
Hepatic
Clearance
(CLH)
Hepatic
Extraction
Ratio
(EH)

20. high EH (Insensitive to Protein Binding)
CLint =1000 L/hr
Hepatic
Clearance
(CLH)
Hepatic
Extraction
Ratio
(EH)

21. high EH (Insensitive to k and t1/2)
CLint =1000 L/hr
Elim.
Rate
Constant
(k)
Half time (t1/2)

22. Hepatic Clearance (CLh) Summary
Low Eh
Sensitive to enzyme activity/concentration (CLint)
Insensitive to hepatic blood flow (Qh)
Sensitive to protein binding (fu)
Sensitive to k and t1/2
High Eh
Insensitive to enzyme activity/concentration (CLint)
Sensitive to hepatic blood flow (Qh)
Insensitive to protein binding (fu)
Insensitive to k and t1/2

23. a b a b

24. Excretion Rate

25. fu vs. Renal Excretion Rate
Total Filtration Rate
Secretion Filtration Rate
Glomerulus Filtration Rate

26. fu vs. “Renal Excretion Rate”
Excretion Rate in units of clearance (volume/hour)
diuretic

27. Total
Secretion
Filtration
Excretion Rate in L/hr units
Excretion Rate in mg/hr units

28. Renal Extraction Ratio (ER)

29. Constant ER Renal Extraction Ratio Excretion Rate Total Excretion Rate
Filtration Rate
Secretion Rate

30. Constant EH

31. Relationships