Lecture 8

Question 1

Drug Metabolism

Answer 1

• Major factor in drug excretion and plasma levels
• Drug inactivation or activation can be connected to it (parent drug being inactivated or activated)
• Mixed actions can also occur from multiple metabolites forming with different activities

Question 2

Where does metabolism occur?

Answer 2

• Wherever metabolic enzymes are present
• Mainly liver
• Also lungs, skin, kidneys, and brain
• Almost every tissue has some metabolic capacity

Question 3

Phase I

Answer 3

-Usually produces a more polar metabolites by introducing or unmasking a functional group
-Excreted if metabolites are sufficiently polar
-Many undergo subsequent reactions
EX: Cytochrome P450 (inserts oxygen), hydrolases (hydrolysis of esters and amides), reductases (nitro, keto, azo)

Question 4

Key Enzymes (4)

Answer 4

1. NADPH-cytochrome P450 reductase - flavoproteins
2. Cytochrome P450 - heme proteins
3. Flavoprotein Monooxygenases - similar reactions as P450 (N-/S- oxidations mainly)
4. Hydrolytic Reactions - cytosolic enzymes in liver, kidney, and plasma that are esterases and amidases

Question 5

Phase II

Answer 5

• Conjugate Reactions
• Conjugates usually are inactive, but can lead to drug activation or toxic metabolites
• Typically drugs metabolize by two or more Phase II enzymes
• Requires co-factors that can be depleted

Question 6

Metabolism Exceptions

Answer 6

-Sometimes Phase I is AFTER Phase II
-Some drugs have functional groups that form a conjugate directly
EX: Isoniazid

Question 7

Acetaminophen

Answer 7

• 5% of acetaminophen that is metabolized by CYP450 is an highly reactive electrophile
• Fast, reactive (toxic) intermediates being formed depends on the amount of glutathione available
• More toxic species are present when patient is an alcoholic

Question 8

Phase I Oxygenases (3)

Answer 8

1. Cytochrome P450 - C and O oxidation, dealkyation, others
2. Flavin-containing Monooxygenases - N-, S-, and P- oxidation
3. Epoxide Hydrolases - Hydrolysis of epoxides

Question 9

Phase II Transferases (5)

Answer 9

1. Sulfotransferases - transfer of sulfate
2. UGT - transfer of glucuronic acid
3. GST - transfer of glutathione
4. NAT - transfer of acetyl group
5. Methyltransferases - transfer of methyl group

Question 10

Other Enzymes (3)

Answer 10

1. Alcohol dehydrogenases - reduction of alcohols
2. Aldehyde dehydrogenases - reduction of aldehydes
3. NQO - reduction of quinones