Pharm - Lecture 4 - drug metabolism

Question 0

Which organ has the highest drug metabolizing enzymes?

Answer 0

Liver

Question 1

What is a prodrug?

Answer 1

a prodrug is a drug that needs to be activated in the body to its active form

Question 2

What are 4 organs with significant amounts of metabolizing enzymes?

Answer 2

Liver, gastrointestinal tract, kidneys, lungs

Question 3

Where in the cell are Phase I enzymes reside?

Answer 3

smooth endoplasmic reticulum

Question 4

Where in the cell do Phase II enzymes reside?

Answer 4

cytoplasm

Question 5

What is the first pass effect?

Answer 5

drug metabolism that occurs in the liver or intestine before the drug can get into the main circulation

Question 6

What required components do P450s need? (5)

Answer 6

cytochrome P450
P450 reductase (flavoprotein)
NADPH
02
drug (substrate)

Question 7

Where is P450 reductase located in the cell?

Answer 7

On the cytosolic side attached to the membrane

Question 8

How many human P450 genes are there?

Answer 8

57

Question 9

What are the major isoforms of cytochrome P450 and the percentage of drugs handled by them? (3 major, 3 minor)

Answer 9

CYP3A: 50%

CYP2D6: 25%

CYP2C9: 15%

CYP1A2, CYP2E1, CYP2C19: 5% each

Question 10

What is Flavin-containing monooxygenase? (FMO)

Where is it localized in cell?

What reaction does it primarily catalize?

Answer 10

FMO is another Phase I enzyme

Localized in smooth endoplasmic reticulum

catalyzes monooxygenation reactions, primarily of soft nucleophiles

Question 11

What types of products do FMO create?

Answer 11

products are more polar and less toxic

Question 12

What are the required components of FMO? (4)

Answer 12

FMO, NADPH, O2, Drug (substrate)

Question 13

How many isoforms of FMO’s are there and what is the major human liver isoform?

Answer 13

5 isoforms, FMO3 is major human liver isoform

Question 14

What are 3 other Phase I enzymes other than P450?

Answer 14

1) Dehydrogenases (ADH and ALDH)
2) Hydrolases (EPHX, Carboxyl esterases, amidases)
3) FMO

Question 15

What are 4 phase II enzymes and their types of conjugation reactions?

Answer 15

UGT: Glucoronidation
SULT: Sulfation
NAT: Acetylation
GST: Glutathione conjugation

Question 16

What is the net effect of most phase II reactions? (2)

Answer 16

Metabolites are usually more polar and inactive or less toxic

Question 17

From highest to lowest, which phase II enzymes handle the most drugs? (4)

Answer 17

1st: UGT
2nd: SULT
3rd: NAT and GST

Question 18

Which cytochrome P450 is the least inducible?

Answer 18

CYP2D6

Question 19

What affect does grape fruit juice have?

Answer 19

Inhibits intestinal CYP3A and thus increases drug bioavailability

Question 20

Are FMO’s able to be induced or inhibited?

Answer 20

no

Question 21

What disease states affect drug metabolism? (5)

Answer 21

Fatty liver disease
hepatitis
Cirrhosis
cancer
infections

Question 22

How is acetaminophen metablized? (3 routes)

Answer 22

1) SULT
2) UGT
3) CYP2E1 converts it to the toxic molecule NAPIQ:

Question 23

What is NAPIQ and how is it metabolized?

Answer 23

NAPIQ is a toxic product of Acetaminophen and CYP2E1. GST metabolizes it