Lecture 8 Flashcards
Biotransformation/Metabolism I
1
Q
Drug Metabolism
A
- 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
2
Q
Where does metabolism occur?
A
- Wherever metabolic enzymes are present
- Mainly liver
- Also lungs, skin, kidneys, and brain
- Almost every tissue has some metabolic capacity
3
Q
Phase I
A
-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)
4
Q
Key Enzymes (4)
A
- NADPH-cytochrome P450 reductase - flavoproteins
- Cytochrome P450 - heme proteins
- Flavoprotein Monooxygenases - similar reactions as P450 (N-/S- oxidations mainly)
- Hydrolytic Reactions - cytosolic enzymes in liver, kidney, and plasma that are esterases and amidases
5
Q
Phase II
A
- 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
6
Q
Metabolism Exceptions
A
-Sometimes Phase I is AFTER Phase II
-Some drugs have functional groups that form a conjugate directly
EX: Isoniazid
7
Q
Acetaminophen
A
- 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
8
Q
Phase I Oxygenases (3)
A
- Cytochrome P450 - C and O oxidation, dealkyation, others
- Flavin-containing Monooxygenases - N-, S-, and P- oxidation
- Epoxide Hydrolases - Hydrolysis of epoxides
9
Q
Phase II Transferases (5)
A
- Sulfotransferases - transfer of sulfate
- UGT - transfer of glucuronic acid
- GST - transfer of glutathione
- NAT - transfer of acetyl group
- Methyltransferases - transfer of methyl group
10
Q
Other Enzymes (3)
A
- Alcohol dehydrogenases - reduction of alcohols
- Aldehyde dehydrogenases - reduction of aldehydes
- NQO - reduction of quinones