Hepatic Clearance

Question 1

What are the two mechanisms by which drugs can be eliminated by the liver?

Answer 1

1. Biotransformation
2. Billiary Excretion

Question 2

What is the function of SLC transporters?

Answer 2

Influx transporters

Question 3

What is the function of ABC transporters?

Answer 3

Efflux transporters

Question 4

Where are Phase I enzymes most concentrated within the liver?

Answer 4

Closer to the central vein (Zone 3)

Question 5

Where are Phase II enzymes most concentrated within the liver?

Answer 5

Closer to portal vein and arterial blood supply (Zone 1)

Question 6

What are the physiological determinants of hepatic clearance?

Answer 6

1. Hepatic blood flow (Qh)
2. Unbound fraction (f(u)b)
3. Intrinsic Clearance (Clint)

Question 7

What aspects of hepatic does the Well-stired Model do a good job at representing?

Answer 7

1. Shows interrelationship of the physiological determinants
2. Allows qualitative predictions of how hepatic clearance changes with changes in physiological determinants

Question 8

Review slide 6 for an equation of the Well-Stirred Model

Question 9

What is the rate-limiting process for the hepatic clearance of high extraction ratio drugs?

Answer 9

Hepatic blood flow (Qh)

Question 10

What factors impact hepatic blood flow?

Answer 10

1. Disease (ex. heart failure)
2. Physiological condtions (food=increased hepatic blood flow; exercise reduces hepatic blood flow)

Question 11

What is the rate-limiting step for hepatic clearance in low extraction ratio drugs?

Answer 11

Factors that are not hepatic blood flow

ex. unbound fraction, intrinsic clearance

Question 12

What factors impact unbound fraction? (affect low extraction ratio drugs)

Answer 12

Unbound fraction changes with:
- Altered affinity for binding
- Altered capacity of binding

Question 13

What factors impact intrinsic clearance?

Answer 13

Intrinsic clearance changes with:
- Inhibition of enzymes (drug interaction, disease)
- Induction of enzymes (drug interaction, food/environmental chemical)

Question 14

What physiological factors affect hepatic blood flow?

Answer 14

Age (older adults have reduction in hepatic blood flow)

Postural change (quick motion from lying down to upright can reduces cardiac output)

Food ingestion increases splanchic blood flow and hepatic blood flow

Exercise redistributes blood away from GI tract (lower hepatic blood flow)

Question 15

What are some disease states that affect hepatic blood flow?

Answer 15

• Diseases that reduce cardac output (heart failure)
• Drugs (can increase or decrease cardiac output due to hemodynamic interactions)
• Intra- and extrahepatic shunting of blood

Question 16

What is the effect of enzyme induction on hepatic clearance?

Answer 16

Enzyme induction increases intrinsic clearance, which in turn increases hepatic clearance

Question 17

What is the effect of enzyme inhibition on hepatic clearance?

Answer 17

Enzyme inhibition reduces intrinsic clearance, which inturn decreases hepatic clearance

Question 18

What factors affect intrinsic clearance?

Answer 18

• Enzyme induction (increase)
• Enzyme inhibition (decrease)
• Size of administered dose (concern in non-linear PK)
• Interindividual differences in metabolism
• Disease states
• Age (neonates and elderly have reduced enzyme activity)
• Nutritional status (deficiencies can reduce enzyme activity)
• Unbound fraction

Question 19

Do drugs with high extraction ratios have high bioavailability?

Answer 19

No, high extraction ratio drugs have low bioavailability (they are metabolized at a greater rate)

Question 20

Do drugs with low extraction ratios have high bioavailability?

Answer 20

Yes, low extraction ratio drugs have high bioavailability (drug is metabolized at lower rate, more reaches the tissues)

Question 21

What is the effect of liver disease on unbound fraction?

Answer 21

The liver synthesizes albumin, a plasma protein that can bind to drugs

In liver disease, albumin production can be lower = increased unbound fraction

Question 22

What is the effect of changes in intrinisic clearance to the hepatic clearance of high extraction ratio IV drugs?

Answer 22

No effect on hepatic clearance or half-life

Question 23

What is the effect of changes in intrinsic clearance to the hepatic clearance of high extraction ratio oral drugs?

Answer 23

Significant changes in Fo, oral clearance, oral AUC

Question 24

What is the effect of changes in instrinsic clearance to the hepatic clearance of low hepatic clearance of low extraction ratio IV drugs?

Answer 24

Significant changes in hepatic clearance and half-life

Question 25

What is the effect of changes in intrinsic clearance to the hepatic clearance of low extraction ratio oral drugs?

Answer 25

Significant changes in oral clearance and oral AUC