Hepatic Clearance Concepts I

Question 1

Describe the anatomical appearance of a liver.

Answer 1

• largest organ in the adult body (~1.5kg)
• anatomically divided into the left and right lobe, which are separated by a falciform ligament.
• functionally segmented according to the distribution of its main vascular and biliary channels.

Question 2

Describe the components of hepatic blood flow, and how they can be modified.

Answer 2

• comprises inflow from the hepatic artery and portal vein, and outflow from the hepatic vein.
• inflow = outflow
• 1350L/min for inflow or outflow for a 70kg man
• how to modify hepatic blood flow: exercise, drugs, hydration, posture.

Question 3

Describe the structure and functions of the sinusoidal sub-structure.

Answer 3

• comprises a radial distribution of hepatocytes, sinusoids and bile canaliculi, which are bounded by the terminal branches of the central vein, portal vein, hepatic artery and bile duct.
• at the other end of the sinusoid is a central venule - wide, low pressure but with the same flow.
• exchange of drug from blood into hepatocytes of the liver occurs within the lobules, the main functional unit of the organ.

Question 4

How to calculate the Kp (ratio of total concentration of compound in the tissue to the total concentration of compound in the plasma at steady state)?

Answer 4

Ct/C

Question 5

Describe the flow of blood in the liver.

Answer 5

1. Upon entering the liver, the blood is drained into the hepatic sinusoids.
2. Screened by specialised macrophages (Kupffer cells) to remove pathogens that got past the GI defence.
3. Plasma is filtered through the endothelial lining of the sinusoids, and bathes the hepatocytes.
4. Hepatocytes contain metabolic enzymes and transporters.

Question 6

Describe the flow of bile in the liver.

Answer 6

1. There is an anti-parallel canalicular duct for collection of bile produced by the hepatocytes.
2. Canalicular bile dumps into the biliary ductules, the main bile duct and eventually into the gall bladder.

Question 7

What can you say about the relationship fo the direction of bile flow and the flow of blood?

Answer 7

they are opposite of one another.

Question 8

Describe the structure and function of hepatocytes.

Answer 8

• large polyhedral cells abundant with subcellular organelles.
• involved with the synthesis, storage, secretion, excretion and modification of both endogeneous and exogeneous material.
• between adjacent hepatocytes, a small bile canaliculus is formed by the membranes of hepatocytes.

Question 9

What happens when the hepatocytes are treated with phenytoin?

Answer 9

enzyme expression in every hepatocyte is increased.

Question 10

What are the factors affecting hepatic clearance?

Answer 10

1. perfusion
2. binding to blood cells (blood and unbound drug - reversible arrow)
3. binding to plasma proteins (unbound and protein-bound drug - reversible arrow)
4. permeation or transport of unbound drug into hepatocytes. (unbound drug that travels from blood to hepatocytes)
5. elimination via secretion into bile (unbound drug in hepatocyte to bile)
6. elimination via metabolism

Question 11

How would you calculate the rate of elimination in the liver?

Answer 11

rate of elimination = CL x C = CLint x Cuh, where CLint= intrinsic hepatocellular eliminating activity

Question 12

(T/F): rate of elimination fo drug within cells is independent of the intracellular unbound concentration, Cuh.

Answer 12

False.

Question 13

How would you calculate the rate of in-vitro metabolism for first-order kinetics?

Answer 13

rate of in vitro metabolism = (Vmax * Csubstrate) / (Km + Csubstrate)

for first-order kinetics, Csubstrate is small (

Question 14

How are CLint, Vmax and Km related?

Answer 14

CLint = Vmax/Km