Lecture 6: Metabolism

Question 1

Blood flow out of the liver

Answer 1

-through hepatic veins into the inferior vena cava

Question 2

Bile flow out of the liver

Answer 2

-out the bile duct

Question 3

Oxygen-rich blood flow INTO the liver

Answer 3

through hepatic artery

Question 4

nutrient rich blood coming from bowel INTO liver

Answer 4

-via portal vein

Question 5

Bile composition

Answer 5

-water
-bile salts
-bilirubin
-fats

Question 6

Bile Fuction

Answer 6

-surfactants
-helps fat digestion
-bilirubin elimination
-drug elimination

Question 7

Bilary excretion into intestine

Answer 7

-gall bladder to cystic duct to duodenum

Question 8

Hepatic blood flow

Answer 8

1.5 L/min

Question 9

Liver tissue

Answer 9

-sinusoid w central vein
-portal triad

Question 10

portal triad

Answer 10

-branch of bile duct
-branch of portal vein
-branch of artery

Question 11

Blood flow in liver tissue

Answer 11

-from portal triad to center vein

Question 12

bile flow in liver tissue

Answer 12

-flows out

Question 13

Kupfer cells

Answer 13

-macrophage cells in liver
-part of reticuloendothelial system

Question 14

Liver sinusoidal endothelial cells

Answer 14

-make up 15-20% of liver cells
-contain many open pores (fenestrae)

Question 15

Sinusoidal capillary

Answer 15

-has holes
-allows direct exchange between blood and hepactocytes

Question 16

Hepatocyte

Answer 16

-synthesis of plasma proteins (albumin, coagulation factors)
-regulation of nutrient balance
-synthesis of bile acids
-detox bilirubin
-detox xenobiotics

-oxireductase-CYP complex in ER

Question 17

Principles of drug metabolism

Answer 17

1. convert lipophilic to hydrophillic
2. can be categorized by one of 4 chemical reactions
3. Is catalyzed by limited munber of enzymes w broad substrate specificity
4. Certain drug-metabolizing enzymes’ expression can be upregulated, leading to inc metabolism of drugs
5. Drug metabolism can be inhibited by drugs
6. gut microbiota mediate some drug metabolism

Question 18

Conversion of lipophilic to hydrophilic

Answer 18

-phase 1: functionalization
-phase 2: conjugation

=excretion into bile or urine

Question 19

Phase 1: functionalization

Answer 19

-adds functional group

Question 20

Phase 2: conjugation

Answer 20

-attaches hydrophillic group to functional group

Question 21

2. chemical reactions of drug metabolism

Answer 21

1. oxidation
2. conjugation
3. Hydrolysis
4. Reduction

Question 22

Oxidation

Answer 22

-add -OH
-usually followed by conjugation

Question 23

Hydrolysis

Answer 23

-cleave

Question 24

Reducation

Answer 24

=O to -O

Question 25

Enzyme that mitigates oxidation

Answer 25

-CYP450

Question 26

Conjugation enzyme

Answer 26

-UDP glucuronosyl transferase (UGT)

Question 27

Hydrolysis enzymes

Answer 27

-carboxyesterase

Question 28

Major reactions of hepatic drug metabolism

Answer 28

-Oxidation
-Conjugation

Question 29

Cyt P450

Answer 29

-#1 catalytic versatility
-highest level in the liver
-mono-oxygenase
-more than 50 but 10 do the most

Question 30

mono-oxygenase

Answer 30

-adds -OH

Question 31

CYP complex

Answer 31

-contains heme group Fe
-responsible for oxidation

Question 32

Major CYP enzymes

Answer 32

-CYP3A4
-CYP2D6

Question 33

CYP3A4 reactions

Answer 33

-aromatic hydroxylation

Question 34

CYP2D6 reactions

Answer 34

-aliphathic hydroxylation
-N-dealkylation
-O-dealkylation

Question 35

Glucuronidation

Answer 35

-UGT
-morphine conjugated to morphine 3-glucuronide

Question 36

Be able to predict where

Answer 36

-rxns occur on molecule

Question 37

Drug metabolism study tools

Answer 37

-metabolite ID in liver
-CYP phenotyping using recombinant CYP

Question 38

Enzyme inducing drugs

Answer 38

-activate transcription factor PXR
-leads to dec exposure to enzyme substrates
-rifampin
-cause of drug drug interactions

Question 39

Enzyme inhibiting drugs

Answer 39

-inhibit activities of drug-metabolising enzyme
-lead to inc substrate drug exposure
-ketoconazole

Question 40

Gut microbiota

Answer 40

-outnumber human cells
-fiber digestion
-mainly reduction and hydrolysis

Question 41

Double peak phenomenon

Answer 41

cause of enterohepatic cycling of drugs and metabolites
-second peak in plasma chart