Drug Metabolism

Question 1

Name 6 types of reactions that happen in phase 1 metabolism

Answer 1

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

Question 2

Name 3 things that the enzyme xanthine oxidase metabolises

Answer 2

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

Question 3

What’s the purpose of phase 1 metabolism?

Answer 3

Functionalisation/activation of drugs

Question 4

Which CYP enzyme metabolises warfarin on the aliphatic branch?

Answer 4

CYP3A4, R-isomer, slower

Question 5

Which CYP enzyme metabolises warfarin on the aromatic part?

Answer 5

CYP2C9, S isomer, faster

Question 6

What’s CYP450 enzymes

Answer 6

Membrane bound enzymes involved in metabolism of hydrophobic drugs

Question 7

List briefly how P450 enzymes work

Answer 7

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?)

Question 8

What happens in an uncoupled reaction?

Answer 8

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

Question 9

What is an enzyme super family?

Answer 9

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

Question 10

What does homology mean

Answer 10

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

Question 11

What is meant by identity?

Answer 11

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

Question 12

Name three enzyme super families

Answer 12

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

Question 13

Name 5 INTRINSIC factors affecting drug metabolism

Answer 13

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

Question 14

Name 6 EXTERNAL factors that affect drug metabolism

Answer 14

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

Question 15

What is the aim of phase 2 metabolism?

Answer 15

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

Question 16

Name 6 reactions involved in phase 2 metabolism

Answer 16

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

Question 17

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

Answer 17

Glucoronidation, due to availability of UDP-glucuronic acid

Question 18

What is the reaction glucoronidation performed by?

Answer 18

UDP-glucuronosyl transferase

Question 19

At what MW are drugs excreted in urine?

Question 20

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

Answer 20

MW >200Da

Question 21

What is glutathione important for?

Answer 21

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

Question 22

Are cytosolic enzymes trimers?

Answer 22

No they’re dimers, microsomal enzymes are trimers

Question 23

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

Answer 23

20isoforms

Question 24

Which exon is variable in UGTs?

Answer 24

Exon 1

Question 25

Where are CYP enzymes mainly found

Answer 25

Liver

Question 26

What are CYP enzymes involved in

Answer 26

Metabolism of hydrophobic drugs