1. MS WinNonLin Assignment
Due Today: Simulated Table in MS Word (.docx) format.
You won’t have to do calculations, but understand what the terms mean.

2. Lecture #10
Hepatic Clearance

3. Outline Hepatic Blood Flow (QH) Liver
Factors that Effect Hepatic Elimination
Intrinsic Clearance
Biliary Clearance
Extraction Ratio
Hepatic Clearance

4. Hepatic Blood Flow (QH)
Liver
GI Tract
Aorta
Vena Cava
Hepatic
Artery
Vein
Portal
Gall Bladder
Bile
Duct
Heart
skin
fat
1 minute to get blood through the systemic circulation. See Table 4-4 in the textbook.

5. Hepatic Blood Flow (QH)
Liver
GI Tract
Aorta
Vena Cava
Hepatic
Artery
Vein
Portal
Gall Bladder
Bile
Duct
Heart
skin
fat

6. Hepatic Blood Flow (QH)
Liver
GI Tract
Aorta
Vena Cava
Hepatic
Artery
Vein
Portal
Gall Bladder
Bile
Duct
Heart
skin
fat

7. Liver Lobes of Liver 5-8 – Right Lobe 2-3 – Left Lobe
Lobes of Liver
5-8 – Right Lobe
2-3 – Left Lobe
4 – Quadrate Lobe
1 – Caudate Lobe

8. Liver Lobule Liver acinus Liver anicus
Central Vein, Hepatic Vein or Hepatic Venule
Liver acinus
Central Vein, Hepatic Vein or Hepatic Venule
Liver anicus #1
Portal Triad #2 #3

9. Liver acinus Q Liver acinus Bile duct Bile canaliculus
Central Vein, Hepatic Vein or Hepatic Venule
Sinusoid
Septal Branch
Space of Disse
Hepatocyte Q
Kupffer cell
Hepatocyte
Bile
canaliculus
Space of Disse
Sinusoidal Lumen
Kupffer cell
Septal = Separating Branch
Hepatocytes
Hepatocytes
Hepatic artery
branch
Portal vein
branch
Bile duct
Endothelial cell
with fenestrae
(100 nm in diameter)
Dendritic
cell
Stellate
cell
Pit cell

10. Liver Zones Zone 1 Liver acinus Zone 1 (Periportal)
Central Vein, Hepatic Vein or Hepatic Venule
Zone 1
Zone 1 (Periportal)
nearest to the entering vascular supply
most oxygenated blood (insensitive to ischemic injury)
susceptible to viral hepatitis.
Specialized hepatocytes
gluconeogenesis
β-oxidation of fatty acids
cholesterol synthesis
haemochromatosis
Hepatic artery
branch
Portal vein
branch
Bile duct

11. Liver Zones Zone 3 Liver acinus Zone 3 (Centrilobular)
Central Vein, Hepatic Vein or Hepatic Venule
Zone 3
Zone 3 (Centrilobular)
Farthest from the entering vascular supply
least oxygenated blood (sensitive to ischemic injury)
Specialized hepatocytes
glycolysis
Lipogenesis
cytochrome P-450-based drug detoxification (CYP2E1)
Hepatic artery
branch
Portal vein
branch
Bile duct

12. Liver Zones Zone 2 Liver acinus Zone 2 (Midzonal)
Central Vein, Hepatic Vein or Hepatic Venule
Zone 2
Zone 2 (Midzonal)
Intermediate between 1 and 3
Necrosis with Yellow Fever
Hepatic artery
branch
Portal vein
branch
Bile duct

13. Factors that Affect Elimination
Perfusion (QH)
Protein and Cell Binding
Permeation/Transport
Metabolism
Secretion into Bile (Excretion)

14. Q Sinusoid 70 L/hr 0.025 L/hr Bile canaliculus
(620 ml/day) ~25 ml/hr L/hr
0.025 L/hr
Bile canaliculus

15. Intrinsic Clearance
Book Version: intrinsic hepatocellular eliminating activity.
My Version: liver cell eliminating activity either through metabolism or excretion.
Unbound drug
metabolism
excretory

16. Michaelis-Menten and Metabolic Intrinsic Clearance (CLint,m)
Liver
fast
slow
E+S ES  P
hepatic
artery
hepatic
vein
portal
vein
Show the derivation of the Michaelis-Menten Equation:

17. Michaelis-Menten vs. Intrinsic Clearance
is the capacity of endogenous enzymes to transform a substance expressed in volume per unit time, since formation of the metabolite is rate limiting for its elimination.
The Clint decreases as substrate increases because we are talking about a volume cleared. More substrate means that it takes more time to clear the volume.
v (mg/hr)

18. Biliary Clearance (CLbile)
hepatocyte
CLint,ex
CLbile
Bile canaliculus

19. Extraction Ratio
Fraction Remaining
Units = Unitless

20. Perfusion-Limited E > 0.7 Non-Restrictive Capacity-Limited
E < 0.3
Restrictive
Causes
Poor Drug Metabolism
Poor Drug Transport
Poor Drug Permeability

21. Extraction Ratios Restrictive Non-Restrictive (Capacity-Limited)
(Perfusion-Limited)

22. Clearance, Extraction Ratio and Q
Non-Restrictive
E=~1
E > 0.7
CLH (mL/min)
Restrictive
E < 0.3
QH (mL/min)

23. Extraction Ratio (E) and fu
Non-Restrictive
Restrictive

24. Liver Enzyme Activity

25. Modeling Hepatic Clearance
Output Conc. after going through the liver
Conc. along Liver
Concentration along the length of liver.
Output concentration.
From Intrinsic Clearance Lecture Fall 2014 (Slide 22) Not sure

26. Well Stirred Model
Well Stirred Model

27. Non-Restrictive (Perfusion-Limited) Hepatic Clearance: High Eh
Can the hepatic clearance (CLH) be greater than hepatic blood flow (QH)?

28. Restrictive (Capacity-Limited) Hepatic Clearance: Low Eh

29. Complexities Permeability Location/Distribution of Transporters
Enterohepatic (Cycle) Circulation

30. barbital
Permeability
Hydrophobicity
enalaprilat

31. Drug Transporters

32. Enterohepatic Circulation (Cycle)
Liver
GI Tract
Aorta
Vena Cava
Hepatic
Artery
Vein
Portal
Gall Bladder
Bile
Duct
Heart
skin
fat
Figure 2-10 in the book.