Nikolic

Question 1

Definition of drug metabolism. Goal.

Answer 1

the process of chemical alteration of drugs or any foreign substance termed xenobiotic inside a living organism. Turn lipophilic drugs into hydrophilic for excretion.

Question 2

Name 3 inter-individual factors of metabolism

Answer 2

1. species
2. genetics
3. sex

Question 3

Name 6 intra-individual factors of metabolism

Answer 3

1. age
2. disease
3. pregnancy
4. stress
5. nutrition
6. enzyme induction/inhibition

Question 4

Major phase I enzyme and major phase II enzyme?

Answer 4

CYP 450 and UDP glucuronyl transferase (for glucuronidation)

Question 5

What kind of reaction is N-dealkylation?

Answer 5

Oxidation (Phase I)

Question 6

What kind of reaction is demethylation?

Answer 6

Oxidation (Phase I)

Question 7

Name a prodrug

Answer 7

Enalapril. The active metabolite is enalalprilate.

Question 8

Where is CYP450 located in a cell?

Answer 8

It’s in the smooth endoplasmic reticulum

Question 9

The E in CYP4502E1 is ___________.

Answer 9

Subfamily

Question 10

The 6 in CYP4502D6 is _________.

Answer 10

isoform/member

Question 11

Primary role of CYP450 is???

Answer 11

metabolism of endogenous compounds

Question 12

Which families of CYP450 are mainly for drug metabolism?

Answer 12

Families 1, 2, 3

Question 13

Families share _____% homology?

Answer 13

> 40% sequence homology

Question 14

Subfamilies hsare _____% homology?

Answer 14

> 55% sequence homology

Question 15

Which enzyme has no meaningful inducer?

Answer 15

2D6

Question 16

Cigarette smoke induces what and the metabolism of what which causes what?

Answer 16

Induces enzyme 1A2, metabolism of Theophylline, causing asthma.

Question 17

Inhibition is maximal when__________________.

Answer 17

inhibitor reaches steady state

Question 18

Describe the active site of P450. “….in the middle of 4….”

Answer 18

Contains heme in hydrophobic pocket. Iron in the middle of 4 pyrrole rings. 5th ligand is thiolate anion from cysteine residue. 6th one occupied by the water molecule. ALL THE ACTIONS HAPPEN ON THE HEME.

Question 19

P450 general interaction:

Answer 19

RH + O2 _ NADPH —–> ROH + NADP+ + H2O

Question 20

What does the flavoprotein NADPH-cytochrome P450 reductase do?

Answer 20

It holds on the the H (electrons) from NADPH (which becomes NADP+) and give them to P450 enzyme one by one to let it form the H2O.

Question 21

Describe the 2 step P450 reaction mech.

Answer 21

1. hydrogen abstraction (that O from P450 taking that H from the drug RH to form OH on P450 itself)
2. oxygen rebound (then giving the OH back to the R drug to form ROH)

Question 22

In monosubstituted aliphatic rings, hydroxylation typically occurs at what 2 positions?

Answer 22

C3 and C4

Question 23

N-dealkylation of benzphetamine

Answer 23

slide 78

Question 24

What to do when you see alkene????

Answer 24

Epoxide. Very reactive electrophile. From very hydrophobic to hydrophilic. Make them ready for glucuronidation. EXAM QUESTION.

Question 25

What’s an NIH shift?

Answer 25

It occurs in aromatic epoxides (arene oxide) in which an epoxide after nucleophile attach becomes a keto or enol.

Question 26

Aromatic hydroxylation. What kind of groups would slow down aromatic hydroxylation and direct to meta position?

Answer 26

Electron withdrawing groups. COOH, NO2, +NR3, X

Question 27

What kind of groups would speed up aromatic hydroxylation and which position(s) would it direct to?

Answer 27

Electron donating groups like OR, OH, NH2, R

Question 28

For drugs with 2 aromatic rings, the more e–(rich/poor) one is usually hydroxylated

Answer 28

Rich, one next to electron donating groups like OH, NH2, OR, R

Question 29

In MAO reactions, is the reactant H2O or O2? And what do you produce?

Answer 29

H2O; H2O2

Question 30

What is the role of MAO?

Answer 30

To metabolize endogenous compounds like catecholamines (dopamine, epinephrine) into alcohols or aldehydes

Question 31

What is disulfiram (Antabuse)?

Answer 31

It’s a treatment of alcoholism. Inhibits aldehyde dehydrogenase, leading to the accumulation of acetylaldehyde. This is what the Asian glow is=====>accumulation of acetyladehyde.

Question 32

Amide hydrolysis is (faster/slower) than ester hydrolysis.

Answer 32

Slower.