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Cancer Pharmacology > Drug Metabolism > Flashcards

Drug Metabolism Flashcards

1
Q

What is a xenobiotic?

A

Anything which is foreign to the body

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2
Q

What happens if a xenobiotic undergoes genotoxic activation?

A

Produces genotoxic carcinogens which bind to DNA and form DNA aducts, damage chromosomes and cause cancer

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3
Q

What happens if a xenobiotic undergoes non-genotoxic activation?

A

It does not directly bind to DNA
Can increase ROS, inflammation, epigenetic silencing, receptor activation and immunosuppression
The change in cellular processes can alter DNA and cause cancer

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4
Q

What are the 4 phases of gut metabolism?

A

Distribution
Absorption
Metabolism
Excretion

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5
Q

What is first pass metabolism?

A

When the drug is absorbed from the gut to the liver for the first time

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6
Q

How can the drug be excreted?

A

In urine from the bladder

In faeces from the gall bladder

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7
Q

What is drug pharmacokinetics?

A

What the body does to the drug

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8
Q

What is drug pharmacodynamics?

A

What the drug does to the body

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9
Q

What is the aim of metabolism?

A

To get a compound which is normally not water soluble and not easily excreted to make it more water soluble so it can be excreted

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10
Q

What enzymes are involved in phase 1 metabolism?

A

P450s

FMO

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11
Q

What enzymes are involved n phase 2 metabolism?

A

GST
UGT
ST

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12
Q

What happens during phase 1 metabolism?

A

Creates or exposes an electrophilic/ nucleophilic group through oxidation or reduction

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13
Q

What do electrophilic groups conjugate with in phase 2 metabolism?

A

GSTs

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14
Q

Where are P450 enzymes located?

A

In the smooth ER

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15
Q

Where are their high concentrations of FMOs?

A

In the liver

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16
Q

Where is the subcellular location of FMOs?

A

In the smooth ER

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17
Q

What are the cofactors of FMOs?

A

NADPH and molecular oxygen

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18
Q

What happens if there is a mutation in FMOs?

A

You cannot metabolise trimethylamine and you secrete it as swear
Odorous

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19
Q

What reactions are P450s involved in?

A

Steroid biosynthesis
Bile acid biosynthesis
Drug/ xenobiotic metabolism
Fatty acid metabolism

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20
Q

Where do P450s receive electrons from?

A

Through their catalytic cycle from P450 OxidoReductase (POR) using FAD and FMN

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21
Q

What P450s are most commonly involved in drug metabolism?

A 
CYP3A4/5
CYP1A2
CYP2D6
CYP2C19 
CYP2C9
22
Q

What fraction of metabolism is caused by UGTs?

A

1/3

23
Q

What is the conjugating moiety of UGTs?

A

Glucuronic acid

24
Q

Where is UGT in high concentration?

A

In the liver, gut and other tissues

25
Q

Where is the subcellular location of UGTs?

A

Smooth ER

26
Q

What is the cofactor of UGT?

A

UDPGA

27
Q

What is the conjugating moiety of sulphotransferases?

A

Sulphate

28
Q

Where is sulphotransferases found?

A

Liver, intestine and platelets

29
Q

Where is the subcellular location of sulphotransferases?

A

Cytosol

30
Q

What is the cofactor of sulphotransferases?

A

PAPS

31
Q

What superfamily do sulphotransferases belong to?

A

SULT

32
Q

What is the conjugating moiety of N-acetyl transferases?

A

Acetyl group

33
Q

What is the cofactor for N-acetyl transferases?

A

Acetyl co-A

34
Q

Where is N-acetyl transferases found?

A

Liver, lung and gut

35
Q

What is the conjugating moiety of methylation?

A

Methyl group

36
Q

What is the cofactor for methylation?

A

S-adenosylmethionine

37
Q

Where is methylation found?

A

In many tissues

38
Q

Why do drug and pro-carcinogens bind to glutathione?

A

To form less toxic conjugates

39
Q

What catalyses the conjugation between the drug and glutathione?

A

GST

40
Q

What are the subcellular locations of glutathione transferases?

A

Mitochondria
ER
Nucleus
Cytoplasm

41
Q

What is phase 0 metabolism?

A

Transport of the drug into the cell via transporters

42
Q

What is phase 3 metabolism?

A

Export of the compounds out of the cell via transporters

43
Q

Name 2 classes of drug transporters

A

SLC and ABC

44
Q

What drugs are used to make another drug more effective via metabolism?

A

Pump inhibitors

45
Q

What is the issue with pump inhibitors?

A

If there is something which needs to be taken up/ removed it cant

46
Q

Name 2 important nuclear receptors

A

CAR

PXR

47
Q

Explain how phenobarbital induces metabolism

A

binds to CAR -> CAR dimerises with RXR -> fires a series of enzymes which will metabolise phenobarbital

48
Q

What is the issue with poor metabolisers?

A

They will experience higher levels of the drug and therefore worse side effects

49
Q

What is the issue with ultra rapid metabolisers?

A

They metabolise the drug too fast for it to take effect

50
Q

How many Ethiopians are ultra rapid metabolisers?

A

1 in 3 because they have multiple copies of the gene

51
Q

In terms of metabolism, what is the issue with tamoxifen?

A

It has to be activated to 4-hydroxy-tamoxifen or endoxifen, however, if you do not have CYP2D6 you cannot do this

52
Q

In terms of metabolism, what is the issue with using mouse models for pre-clinical trials?

A

They have a lot more different types of P450 than humans so they metabolise drugs differently - drugs are therefore toxic to humans

Cancer Pharmacology (13 decks)

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