Drug metabolism Lecture: 08 14 2014

Question 1

3 things that Drug metabolism does to drugs?

Answer 1

1. Alters pharmacodynamics properties
   
   • inactivate OR activate (prodrugs)
2. Alter pharmacokinetic properties
   
   • increase clearance (shorten half-life)-
     especially with lipophilic drugs.
3. Affects toxic properties
   
   • usually detoxifies EXCEPT for
     Acetaminophen

Question 2

Phase I Reaction (metabolic reaction)

Answer 2

FUNCTIONALIZATION:
-introduce/expose a polar functional group
(OH, COOH, NH2, or SH) to parent compound.

Products may still be active.

Typically occur in the ER of hepatocytes.
- enzymes also known as MICROSOMAL ENZYMES because they are found in the microvesicles formed by the ER. (AKA microsomes)

Requires Oxygen and NADPH

Question 3

Phase I reaction enzymes:

Answer 3

CYP450

• oxidizer
• promiscuous (low substrate specificity)
• SLUGGISH catalysts and rxns are slow.

CYP3A4 is responsible for most metabolism.

Question 4

What induces Phase I enzymes?

Answer 4

Drugs, Environmental chemicals, pollutants, dietary factors, increased transcription, decreased degradation.

• Charcoal-Broiled food
• Cruciferous vegtables
• Cigarette smoking
• Chornic Alcohol Consumption
• St. John’s Wort (CYP3A)

Question 5

What inhibits Phase I enzymes

Answer 5

Certain drugs and Grapefruit juice (CYP3A)

Question 6

Phase II reaction (metabolic reaction)

Answer 6

CONJUGATION:
-conjugation of endogenous compounds to phase I products to make highly polar conjugates.

Typically occur in the cytosol of hepatocytes.

Question 7

What are the more important Phase II conjugation reactions?

Answer 7

1. Glucuronidation
   
   • enzyme: UDP-glucuronic acid
2. Glutathione conjugation
   -enzyme: Glutathione-S-transferase
   
   • conjugation of reactive electrophilic
     compounds with tripeptide GSH.
     -Major detoxification pathway for drugs and
     carcinogens.
     -binds to the radicals

Question 8

Isoniazid (INH)

Answer 8

INH does Phase II acetylation –> Phase I (hydrolysis).

Resutls in compound that is highly reactive and can cause hepatocyte death (but it is acetylated)

Question 9

Acetominophen (Tylanol)

Answer 9

Phase II reactions help eliminate drug BUT it does make a reactive electrophilic compound -
- bulk is detoxified via Glutathione (GSH
conjugation). HOWEVER, a small amount
escapes and creates a compound that
damages the liver.

Antidote: Cysteamine and N-acetylcysteine
- Glutathione drugs

Question 10

Factors that affect metabolism?

Answer 10

1. Genetic factors
   
   • defects/ polymorphisms
2. non-genetic factors
   
   • Age, disease
     - Disease: cardiac (decrease blood flow to liver), any liver damage, Pulmonary disease, heavy metal poisoning and porphyria.
3. Environmental Determinants:
   -Dietary factors (cigarrete smoking, alcohol,
   grilled/broiled food)
   - Environmental factors (pollution)
   - Drug-Drug interactions:
   - Drug- endogenous interactions

Question 11

two drugs for which there are well-defined genetically determined differences in metabolism?

Answer 11

1. Isoniazid –polymorphism of N-acetyltransferase 2 gene (phase II rxn)
   
   • slow
2. Desbrisoquin
   
   • CYP2D6 polymorphism (phase I rxn)
     
     • slow