6 drug metabolism

Question 1

What does drug metabolism do?

Answer 1

1. inactivation
2. activation
3. maintenance of activity

Question 2

What is the major source of first pass metabolism?

Answer 2

liver

Question 3

What happens in phase 1 reactions? Where are the enzymes for phase 2?

Answer 3

adding of functional group

• equal, lower or higher activity
• makes drugs more hydrophilic and provides functional group used to complete phase 2 reactions

-found in ER (liver and intestine)

Question 4

What happens in phase 2? Where are the enzymes for phase 2?

Answer 4

conjugation reaction

• follows phase 1
• some already have functional groups and go directly to phase 2
• example functional groups: glucuronic acid, glutathione, sulfate group, and acetyl group
• found in cytoplasm

Question 5

Are the drugs more lipophilic or hydrophilic after metabolism?

Answer 5

hydrophilic

-net effect is that a lipophilic drug is converted to more hydrophilic metabolite that is easily eliminated in urine

Question 6

What are the three types of phase 1 reactions?

Answer 6

1. microsomal oxidations
   - hydroxylation reactions
2. non microsomal oxidations
   - alcohol oxidation
3. hydrolysis reactions (require water)
   - esterases
   - amidases

Question 7

Microsomal oxidation reactions use what type of enzymes?

Answer 7

cytochrome P450 enzymes

• 57 isoforms
• mixed-function oxidase system (MFO)
• promiscuity

Question 8

How are microsomes isolated?

Answer 8

tissue homogenization and differential centrifugation

-vesicles formed from ER membrane

Question 9

What does a microsomal drug OXIDATION with cytochrome P450 enzymes need? What happens?

Answer 9

NADPH, P450, O2

• one oxygen atom incorporated into durg substrate and one oxygen into water
• ends with hydroxylated drug metabolite

Question 10

What happens in a non-microsomal oxidation reaction such as in alcohol OXIDATION?

Answer 10

ethanol–>acetaldehyde
-alcohol dehydrogenase (most important liver enzyme to metabolize alcohol, some alcohol is met by catalase and CYP2E1)

acetaldehyde–>acetate
acetaldehyde dehydrogenase

Question 11

What happens in phase 1 HYDROLYSIS reactions?

Answer 11

when esterases and amidases are hydrolyzed they have a PABA metabolite which competes with sulfonamide for drug site of action and leads to reduced therapeutic effectiveness

Question 12

How does liver disease affect drug metabolism?

Answer 12

impact on microsomal oxidases

Question 13

HOw does cardiac disease affect drug metabolism?

Answer 13

impact on hepatic blood flow

Question 14

DO neonates and geriatric patients have differnet expression of enzymes?

Answer 14

yes

Question 15

What factors increase metabolism?

Answer 15

• environmental pollutants
• tabacco smoke
• charcoal-broiled meats

Question 16

What inhibits metabolism?

Answer 16

1. competitive inhibition
   - one drug can compete for enzyme with co-administered drug-reversible
2. non-competitive inhibition
   - permanent inhibition of enzyme
   - covalent modification
   - irreversible

Question 17

Active drug vs inactive drug

Answer 17

Active: very lipid soluble
Inactive: less lipid soluble

Active: less polar
Inactive: more polar

Active: less ionized
Inactive: more ionized

Active: weak electrolyte
Inactive: strong electrolyte

Active: more able to penetrate cell membrane
Inactive: less able to penetrate cell membrane