Drug Metabolism

Question 1

Drug metabolism

Answer 1

Chemical transformation of venobiotic (i.e. drug) within living organism
Most drugs: enzyme based
Some drugs: non-enzyme based
Enzymes usually found in hepatocytes

Question 2

Inactivation

Answer 2

Lipid soluble (hydrophobic) -> less lipid soluble (hydrophilic)
Facilitate excretion via kidney (decreases liklihood it will be reabsorbed by tubule so it will stay in urine and be excreted)

Question 3

Activation

Answer 3

Inactive drug-active form
Ex: L-dopa -> active dopamine
Clopidogrel (inactive prodrug) -> active metabolite

Question 4

Major site of biotransformation

Answer 4

ER of hepatocytes in the liver

Question 5

Phase I reactions

Answer 5

Introducing/exposing a new functional group

Amines, hydroxyls, sulfhydrals

Question 6

Phase II reactions

Answer 6

Conjugation reaction
Large molecule gets conjugated onto the functional group
Glucuronic acid, glutathione, sulfate group, acetyl group
Most phase II enzymes are in the cytoplasm, but some can be in ER

Question 7

Microsomal Oxidations

Phase I reactions

Answer 7

Cytochrome P450 enzymes
OXIDATIVE reaction (O2 gets incorporated into drug molecule as hydroxyl group, the other into water)
Mainly found in ER (in liver and intestine)
Mixed-function oxidase system
There is promiscuity between P450 isoforms
NADPH is involved

Question 8

Non-microsomal oxidations

Phase I reactions

Answer 8

No CYP450
Ex. Alcohol oxidation
Alcohol dehydrogenase (in cytosol), acetaldehyde dehdrogenase (in mitochondria)
(remember there is a cyp that metabolizes alcohol, but its not as important as alcohol dehydrogenase)

Question 9

Hydrolysis

Phase I reactions

Answer 9

Requires water
Esterases and Amidases
PABA is a common metabolite
Clinical significance: PABA is structually similar to sulfanilamide (anti-microbial) and thus drugs that metabolize to PABA can compete wtih it. Decreases anti-microbial effects of sulfanilamide

Question 10

Conjugations

Phase II reactions

Answer 10

Functional group from phase I combines with endogenous substrate
Flucuronic acid conjugation
Acetylation
Sulfation
Flutathione conjugation

Question 11

Induction of Drug Metabolism

Answer 11

Typically involved CYP450s
Enhanced rate of synthesis or reduced rate of degradation = increased activity of the enzymes
Inducing factors:
- Environmental pollutants
-Tobacco smoke
-Char-broiled meat
Clinical significance: Altered dosing

Question 12

Inhibition of Drug Metabolism

Answer 12

Competeitive: one drug can compete for enzyme with co-administered drug. REVERSIBLE
Non-competetive: permanent inhibition of enzyme, covalent modification. IRREVERSIBLE. Protein needs to be resynthesized

Question 13

Active drug

Answer 13

(Parent drug)

• Very lipid-soluble
• Less polar
• Less ionized
• Weak electrolyte
• More able to penetrate membrane

Question 14

Inactive drug

Answer 14

(Drug metabolite)

• Less lipid-soluble
• More polar
• More ionized
• Strong electrolyte
• Less able to penetrate cell membrane