Drug induced hepatic disease and enzyme interactions

Question 1

What is hepatic clearance and the 3 factors associated with it

Answer 1

Liver removal of drugs/xenobiotics from blood is termed hepatic clearance (ClH)

3 Factors:
– Liver blood flow
– Liver intrinsic clearance
– Fraction of drug not bound to albumin

Question 2

What is meant by high extraction drugs and the consequences thereof

Answer 2

Drugs/xenobiotics rapidly cleared in a single pass through the liver.

Oral administration of drugs/ xenobiotics is inefficient – must administer IV/IM.

Question 3

What is meant by low extraction drugs and examples thereof

Answer 3

1. These drugs are efficiently absorbed when given orally.
2. Thus bioavailability of orally administered drugs is high.

• Diazepam
• Phenytoin
• Theophylline
• Bilirubin

Question 4

Explain the steps of liver biotransformation and elimination of drugs

Answer 4

1. Transport of drugs/xenobiotics from blood
2. Biotransformation in the liver - Phase 1 and 2
3. Biliary excretion
4. Efflux to blood for eventual renal excretion

Question 5

Explain phase 1 of liver biotransformation

Answer 5

Direct modification of primary structure via oxidative reactions
- Cytochrome P450

Often rate-limiting, located in ER
* May eliminate or generate toxic molecules
* Account for many drug-drug interactions

Question 6

Explain phase 2 of liver biotransformation

Answer 6

Catalyze covalent binding of drugs to polar ligands (“transferases”)

• Increase water solubility
• Enzymes generally in ER, some cytosolic

Question 7

What are the 2 methods of drug drug interactions and there consequences

Answer 7

Competitive inhibition of CYP
– Drug A increases toxicity of drug B

Induction of CYP
– Increased elimination of drug
– Increased production of toxic metabolites