E1 L5: Hepatic Drug Metabolism

Question 1

Oxygen rich blood flows into the liver through the

Answer 1

Hepatic artery (20%)

Question 1

blood flows out of the liver through

Answer 1

Hepatic veins

Question 2

Nutrient rich blood coming from the bowel flows into the liver via

Answer 2

Portal vein (80%)

Question 3

Bile composition

Answer 3

Water
Bile salts
Biirubin
Fats

Question 4

Bile function

Answer 4

Surfactants
Helps fat digestion
Bilirubin elimination
Drug elimination

Question 5

Portal triad

Answer 5

Hepatic vein, bile duct, and hepatic artery

Question 6

Kupffer cell

Answer 6

Resident macrophage of the liver
Deal with bacteria

Question 7

Bile flows from ____ and collects in the bile duct

Answer 7

Central vein

Question 8

Lots of holes (fenestrae)
100-150nm (big holes)
Because of big holes - many molecules, including drugs, can leave the blood vessel and reach hepatocytes

Answer 8

Sinusoidal cells

Question 9

Kupffer cell part of what system?

Answer 9

Reticuloendothelial system (RES)

Question 10

Major cell of drug metabolism

Answer 10

Hepatocytes

Question 11

70% of liver cells
Form Liver’s major metabolic and functional core (glucose metabolism, lipid metabolism)
Synthesis of plasma proteins such as albumin

Answer 11

Hepatocytes

Question 12

Site where drug metabolizing enzymes are expressed and are responsible for drug metabolism

Answer 12

Hepatocyte
CYP450 - ER of hepatocyte
UGT - ER of hepatocyte

Question 13

Principles of drug metabolism: Converts _____ chemicals into _____ which are readily excreted in urine or bile

Answer 13

Lipophilic -> hydrophilic

Question 14

Certain compounds have ___ _____ effect, meaning they cannot be metabolized

Answer 14

First past

Question 15

When a drug can be metabolized:

Answer 15

Chemical structure is modified
Goes under phase II reaction
eliminated into urine
Pumped into blood side

Question 16

What two types of elimination makes up 90% of elimination

Answer 16

Hepatic metabolism and renal
(the rest are drugs that do not make it through eliminated in bile)

Question 17

T/F: You do not always have to do phase I followed directly by phase II

Answer 17

True
-If chemical already has hydroxy, can go directly into phase II

Question 18

4 major pathways of metabolism

Answer 18

Oxidation
UDP glucuronosyl transferase (UGT)
Hydrolysis
Reduction

Question 19

What are the most common pathways of drug metabolism

Answer 19

Oxidation and conjugation

Question 20

Hydrolysis mech

Answer 20

Ester group; add water, bond is cleaved and becomes carboxylic acid and alcohol
(Enzyme: Carboxyesterase)

Question 20

Oxidation mech

Answer 20

Hydroxyl
Typically mediated by CYP450

Question 20

Conjugation mech

Answer 20

Attach hydrophilic group to chemical
Usually mediated by UGT

Question 21

Reduction mech

Answer 21

Undergoes reduction (keto group becomes alcohol)
Major enzyme: Carbonyl reductase

Question 22

Where do metabolism pathways occur?

Answer 22

Liver

Question 23

Two major enzyme classes in metabolism

Answer 23

CYP450 and UGT

Question 24

Ranks 1st in catalytic versatility and the # of drugs it detoxifies among different enzymes Highest level of drug metabolizing - is found in the liver (ER) among different tissues

Answer 24

Cyp450

Question 25

Mono oxygenase

Answer 25

Less than 10 enzymes are responsible for drug metabolism

Question 26

Reactions mediated by P450

Answer 26

Aromatic hydroxylation Aliphatic hydroxylation N-dealkylation O-dealkylation

Question 27

Cyp450 phenotyping

Answer 27

Add drug to different tubes - see which drug exhibits the best enzyme activity

Question 28

Enzyme inducing drug:

Answer 28

Rifampin Activates transcription factor PXR/ leading decreased exposure to enzyme substrates

Question 29

Enzyme inhibiting drug

Answer 29

Ketoconazole -Leads to increased substrate drug exposure

Question 30

A collective term for microorganisms in human gut

Answer 30

Gut microbiota

Question 31

The gut microbiota mediates certain drug metabolism, mainly -

Answer 31

Reduction and hydrolysis

Question 32

Outnumber human cells by 3x Involved in various biological functions, e.g. digestion of fiber

Answer 32

Gut microbiota

Question 33

Double peak phenomenon is caused by

Answer 33

Enterohepatic cycling

Question 34

Q: T/F: Kupffer cells are the primary cells in the liver responsible for drug metabolism

Answer 34

False - hepatocytes

Question 35

Q: Choose two main (most common) drug metabolism reactions in the liver Oxidation Reduction Hydrolysis Conjugation

Answer 35

Oxidation - mediated by P450 conjugation - mediated by UGT

Question 36

Q: T/F: Among CYP450 enzymes, CYP3A4 metabolizes the largest fraction of drugs

Answer 36

True

Question 37

Q: T/F: The portal triad comprises the bile duct, portal vein, and central vein

Answer 37

False - bile duct, portal vein, hepatic artery

Question 38

Q: T/F: Enzyme inducers of CYP3A4 would likely decrease the systemic exposure of CYP3A4 substrate

Answer 38

True (rifampin)

Question 39

Q: T/F: Enzyme inhibitors of CYP3A4 would likely increase the systemic exposure of CYP3A4 substrate

Answer 39

True