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Flashcards in Drug Metabolism Deck (26)
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1
Q

Name 6 types of reactions that happen in phase 1 metabolism

A

1) oxidations (esp CYP450)
2) hydrolysis
3) hydration
4) dethioacetylation
5) isomerisation
6) reduction (rare)

2
Q

Name 3 things that the enzyme xanthine oxidase metabolises

A

1) theophylline
2) theobromine (in tea)
3) caffeine

3
Q

What’s the purpose of phase 1 metabolism?

A

Functionalisation/activation of drugs

4
Q

Which CYP enzyme metabolises warfarin on the aliphatic branch?

A

CYP3A4, R-isomer, slower

5
Q

Which CYP enzyme metabolises warfarin on the aromatic part?

A

CYP2C9, S isomer, faster

6
Q

What’s CYP450 enzymes

A

Membrane bound enzymes involved in metabolism of hydrophobic drugs

7
Q

List briefly how P450 enzymes work

A

1) substrate binds to protein causing iron low spin to high spin
2) (6-5) now a vacant site for O2 binding
3) reduction by P450 reductase is required before dioxygen binds
4) second reduction step occurs following dioxygen binding
5) hydroxylation (>1?)

8
Q

What happens in an uncoupled reaction?

A

NADPH and dioxygen are consumed but substrate is not oxidised. (Under most conditions these reactions are small proportion of catalytic cycles)

9
Q

What is an enzyme super family?

A

The whole group of enzymes that catalyse the same or similar type if reaction using a similar mechanism and are related by primary sequence homology or identity

10
Q

What does homology mean

A

When sequences are aligned, an amino acid in a particular position is conserved by type e.g leucine could be substituted for isoleucine or valine but not arginine

11
Q

What is meant by identity?

A

When sequences are aligned, an amino acid in a particular position is always the same e.g leucine must be leucine

12
Q

Name three enzyme super families

A

1) CYP enzymes (various oxidative reactions)
2) UDP-glucoronsyl transferases (glucoronidation)
3) glutathione-S-transferase (conjugation with glutathione)

13
Q

Name 5 INTRINSIC factors affecting drug metabolism

A

1) Age
2) hormonal and gender differences
3) genetic variability of CYP enzymes
4) differences between races/populations and sub-population
5) individual differences

14
Q

Name 6 EXTERNAL factors that affect drug metabolism

A

1) diet and nutritional status
2) method of cooking
3) alcohol and smoking
4) co-admin of drugs
5) exposure to drugs, solvents
6) diseases e.g alcoholism- liver

15
Q

What is the aim of phase 2 metabolism?

A

Detoxify drugs and/or allow excretion by adding a water solubilising group

16
Q

Name 6 reactions involved in phase 2 metabolism

A

1) glucoronidation (nucleophiles)
2) glutathione conjugation (electrophiles)
3) amino acid conjugation
4) sulfation
5) acetylation
6) methylation (rare)

17
Q

What’s the most common phase 2 reaction and why is it the most common?

A

Glucoronidation, due to availability of UDP-glucuronic acid

18
Q

What is the reaction glucoronidation performed by?

A

UDP-glucuronosyl transferase

19
Q

At what MW are drugs excreted in urine?

A
20
Q

What MW do drugs have to possess in order to be excreted in bile

A

MW >200Da

21
Q

What is glutathione important for?

A

Maintenance of reducing environment (protection against radicals, reactive oxygen species etc)

22
Q

Are cytosolic enzymes trimers?

A

No they’re dimers, microsomal enzymes are trimers

23
Q

How many isoforms of GST (glutathione-s-transferase) are found in humans?

A

20isoforms

24
Q

Which exon is variable in UGTs?

A

Exon 1

25
Q

Where are CYP enzymes mainly found

A

Liver

26
Q

What are CYP enzymes involved in

A

Metabolism of hydrophobic drugs