L25 - Liver Function - Metabolism

Question 1

How do molecules reach the liver? What type of molecules?

Answer 1

Through the hepatic artery and portal vein
- endogenous and ingested molecules and compounds

Question 2

What happens to the molecules when they reach into the liver?

Answer 2

Some are secreted into bile, most reabsorbed in the SI

Question 3

What molecules are metabolised by liver enzymes?

Answer 3

Lipophilic molecules (and drugs)
- to form polar products excreted in the urine

Question 4

What are the two stages to the metabolism?

Answer 4

• phase I
• phase II

Question 5

What are reactions and products like during phase I?

Answer 5

Catabolic - oxidation, reduction or hyrdolysis
Product - still or even more reactive

• mainly applicable to lipid soluble molecules (has to enter cells)

Question 6

What happens during phase I reactions?

Answer 6

Introduces a functional group - provide point of conjugation

Question 7

What are reactions carried out by in phase I?

Answer 7

Hepatic microsomal enzymes (found in ER inside hepatocytes)

Question 8

What is the main microsomal enzyme from?

Answer 8

Cytpchrome P450 family (CYP enzymes)

Question 9

What is the (CYP) Cytochrome P450 monooxygenase system?

Answer 9

• family of haem enzymes
• different members of the family

Question 10

What do cytochrome P450 enzymes differ in?

Answer 10

• a/a seq
• substrate specificity
• susceptibility to inducers and inhibitor

Question 11

What does variations in expression and polymorphic forms of CYP enzymes result in?

Answer 11

Species and inter-individual variation

-important implications in drug testing and drug response

Question 12

What is the monooxygensae P450 cycle?

Answer 12

• P450 w/ Fe3+ combines with drug
• e- from NADPH P450 reductase
• Fe reduced to Fe2+
• combines w/ O2, proton and 2nd e-
  = FeOOH-DH
• combines w/ proton = water and (FeO)3+DH
• (FeO)3+ extracts H+ to release DOH and regenerate P450

Question 13

What are the Phase II reactions?

Answer 13

Anabolic
- involve conjugation (attachment of substituent group)
E.g/ glucuronyl, sulphate, methyl or acetyl group

Question 14

What are most products like after phase II reactions?

Answer 14

Inactive

Question 15

What is enterohepatic recirculation?

Answer 15

Hydrophilic conjugates are secreted into bile, delivered to SI, conjugation is removed and molecules/drug reabsorbed

Question 16

What are racemic mixtures?

Answer 16

Molecules and drugs that exist in mixrtues of steroisomers

Question 17

What can steroisomers have?

Answer 17

Different pharmacological effects, metabolised differently

Question 18

What is an example of s drug that is a racemic mixture?

Answer 18

Warfarin
- exists as R&S enantiomers
- metabolised by different CyP450 enzymes

Question 19

What potential is there due to steroisomers?

Answer 19

Large range of srug interactions and effects of polymorphism

Question 20

What is the presystemis firstpass metabolism?

Answer 20

Food/drugs entering the gut are absorbed into SI and pass into the blood

Question 21

What happens to the blood in presystemic firstpass metabolism?

Answer 21

Carried to the liver by hepatic portal bein

Question 22

What are food/drugs metabolised by before they enter the systemic circulation?

Answer 22

Hepatic mircosomal enzymes

Question 23

What does the presystemic firstpass metabolism mean for a drug given orally compared to a drug given iv?

Answer 23

Orally - higher - as metabolised
Iv - lower - direct to blood

Question 24

What does the presystemic firstpass metabolism mean for patients with decreased GI/liver function?

Answer 24

Lower motility - less absorption to blood
Higher motility - more absorption = lower dosage

Question 25

What are prodrugs?

Answer 25

Drugs which only become active once metabolised by microsomal enzymes

Question 26

What can metabolism cause?

Answer 26

Change in pharmacological action

Question 27

What are SNPs amd where are they commonly found?

Answer 27

Single nucleotide polymorphisms
- CYP450 enzymes

Question 28

What can SNPs give rise to?

Answer 28

Different polymorphic forms which metabolise at different rates (fast, intermediate, slow)

Question 29

What does a fast metaboliser have an effect on an active drug or a produrg?

Answer 29

Active drug - higher dose, inactivate more
Prodrug - toxic inc, exceeds therapeutic dose

Question 30

What does a slow metaboliser have an effect on an active drug or a produrg?

Answer 30

Active drug - lower dose, may get toxic as API stays longer
Prodrug - decreases

Question 31

What are dietary, lifestyle and medicinal inducers of CYP450?

Answer 31

• brussel sprouts
• smoking
• st john’s wort

Question 32

What are dietary inhibitors of CYP450?

Answer 32

Grapefruit juice

Question 33

What can affect metabolism of other compouds/drugs?

Answer 33

Several drugs can increase the activity of the CYP enzymes

Question 34

How are enzyme inducers useful?

Answer 34

Phenobarbital induces glucuroyl transferase
- can be administered to premature babies to increase cojugation and removal of bilirubin

Question 35

How are enzyme inducers harmful?

Answer 35

• coadministered drugs may be metabolised too quickly = reducing effect
• any toxic metabolites will be increased

Question 36

What are paracetamol metabolites?

Answer 36

Highly hepatotoxic
- toxicity of overdose increased in patients with chronic alcohol consumption

Question 37

What are examples of enzyme inducers?

Answer 37

Rifampicin (antibiotic) and warfarin (anticoagulant)

Question 38

What does carbamazepine induce?

Answer 38

Its own metabolism
- required to start at a losw dose then increase

Question 39

What can inhibition of enzyme activity do?

Answer 39

Prolong activity of a co-administered drug

Question 40

What is an example of an enzyme inhibitor?

Answer 40

HIV medications are potent inhibitors of CYP450
Metronizaole - S-warfarin
Omeprazole - R-warfarin