Phase 1 and 2 Metabolism

Question 1

What is Phase 1 metabolism?

Answer 1

reactions which involve oxidation, reduction and hydrolysis
- most of these reactions occur in the liver but can also occur in the gut wall, blood plasma and other tissues

Question 2

What structures are most prone to oxidation? What structures are most prone to reduction? What structures are prone to hydrolysis?

Answer 2

oxidation
- N-methyl groups, aromatic rings, the terminal positions of alkyl chains and the least hindered positions on alicyclic rings

reduction
- nitro, azo and carbonyl groups

hydrolysis
- amides via peptidases
- esters via esterases

Question 3

What are monooxgenase?

Answer 3

are haemoproteins - contain haem and iron

enzymes which catalyse a reaction that splits molecular oxygen, such that one of the oxygen atoms is introduced into the drug and the other ends up in water

Question 4

How are amines, ethers and thioethers metabolised?

Answer 4

dealkylation via monooxygenases

amines
- are oxidised to an aminal intermediate
- aminal is broken down into an imine and amine

ether
- is oxidised into hemiacetal
- hemiacetal is hydrolysed to aldehyde and alcohol

thiother
- is oxidised into a thiohemiacetal
- thiohemiacetal is hydrolysed to aldehyde and thiol

Question 5

How are aliphatic and alicylic groups metabolised?

Answer 5

oxidation of the exposed alkyl groups or exposed region of the cycloalkyl rings

Question 6

How are unsaturated carbons metabolised?

Answer 6

oxidation
- alkenes, alkene rings and benzene form epoxides which can be broken down into diols

Question 7

What are flavin monooxygenases?

Answer 7

are proteins that oxidise heteroatom
- N, P, S

Question 8

How are amines metabolised?

Answer 8

amines are oxidised by flavin monooxygenases
- end products has a nitro group (NO2)HO

Question 9

How are thiols metabolised?

Answer 9

thiol - methyl sulphide - sulphoxide - sulphone

dithiol - disulphide

Question 10

How are alcohols and primary amines metabolised?

Answer 10

primary alcohol - aldehyde - carboxylic acid

secondary alcohol - ketone

primary amine - aldehyde

Question 11

Why is N-acetyl-p-benzoquinone imine (NAPQI) toxic?

Answer 11

NAPQI is an alkylating agent
- prevent cell division by crosslinking strands of DNA

reacts with N7 of guanine
- most nucleophilic region

Question 12

What groups undergo glucuronidation?
common vs uncommon

Answer 12

common
- phenol, alcohol, carboxylic acid, thiol, sulphonamide, hydroxyl amine

uncommon
- amide, amine

Question 13

What groups undergo sulphoconjugation?

Answer 13

phenol
alcohol
amine

Question 14

How does glucuronidation occur?

Answer 14

compounds reacts with UDP glucuronate with glucuronyltransferase catalysing the reaction

Question 15

Why are epoxides produced via phase 1 metabolism an issue? How can they be removed?

Answer 15

epoxidation of double bonds are problematic
- nucleophiles can react with the positive C in the 3 membered ring of the epoxide
= leads to alkylation of the guanine

can be removed by glutathione
- acts as an electrophile to react with the epoxide

Question 16

What are the types of phase 2 reactions?

Answer 16

glucuronidation
sulfation
methylation
acetylation
conjugation with glutathione
conjugation with amino acids

Question 17

How does metabolism affect enterohepatic circulation and excretion?

Answer 17

enterohepatic circulation is a feedback loop in which substances are absorbed by the gut, expelled with bile and are reabsorbed by the gut again

drugs with MW<300 is excreted in urine via kidneys
drugs with MW>300 is excreted by bile in faeces via intestine

glucuronide conjugates have 2 possible fates
- excretion in faeces as glucuronic acid adds weight
- hydrolysis back to the parent drug by beta glucuronidase
= e.g. chloramphenicol