drug metabolism

Question 1

what are xenobiotics and what are they usually?

Answer 1

• drugs/foreign compounds

- usually lipophilic

Question 2

what does metabolism do?

Answer 2

• tends to reduce or eliminate pharmacological activity
• converts lipophilic chemicals to polar derivatives
• these are readily excreted

Question 3

what organ is the major site of drug metabolism?

Answer 3

• liver
• hepatic first pass metabolism can be extensive
• if drug is all metabolised in hepatic first pass, might habe no biological effect in kidneys

Question 4

what do phase 1 reactions do? give examples

Answer 4

• introduces a functional group to the molecule
• often inactiavtes chemicals
• after phase 1 there is a change in polarity
• oxidation/reduction
• hydrolysis

Question 5

what does oxidation and reduction do?

Answer 5

adds new functional groups -

serves as attachment for phase 2 reactions

Question 6

what does hydroylsis do?

Answer 6

unmasks the functional group

Question 7

what are cytochrome P450 enzymes? where are they found?

Answer 7

• important enzymes in phase 1 metabolism
• found in liver
• multiple isoenzymes
• certain drugs that can inhibit/induce CYP450 enzyme system (smoking –> cancer)

Question 8

what do oxidation reactions generally start with?

Answer 8

hydroxylation step catalysed by P450 enzymes

Question 9

describe how the cytochrome P450 enzyme works

Answer 9

1. substrate binds to ferric on P450 enzyme
2. electron reduces the ferric
3. oxygen binds to P450, ferrous is formed in process
4. further reduction occurs to form negatively charged oxygen (RDS) and ferric again
5. ferric donates electron to oxygen –> form polar molecule
6. oxygen cleaved –> reacts with 2 protons to form water
7. drug then released from system in hydrolysed form

Question 10

what is the difference between aliphatic and aromatic?

Answer 10

aliphatic - straight chains of carbon atoms

aromatic - ring systems of carbon atoms

Question 11

describe 2 hydroxylation reactions

Answer 11

1. first reaction inactivated the pentobarbitone drug by adding an OH group to the penultimate carbon
2. second reaction is the activation of paracetamol from prodrug Acetanilide by adding OH group to ring itself

Question 12

describe what happens in methylation reactions

Answer 12

a methyl is removed from the nitrogen or from the oxygen depending on the drug

Question 13

what determines how much morphine a pt gets from codeine?

Answer 13

• codeine is a prodrug and is activated by P450 enzymes

- depends how effective each person’s P450 enzymes are as to how much of an effect the morphine gives someone

Question 14

describe N-oxidation

Answer 14

• nitrogen becomes oxidised and forms a dative covalent bond with oxygen atom
• creates a very polar, lipophilic molecule that can be excreted

Question 15

what is ethanol oxidised to?

Answer 15

acetaldehyde using alcohol dehydrogenase

Question 16

what do reduction and hydrolysis reactions do?

Answer 16

reduction: breaks molecule by adding electrons into system
hydrolysis: also severs the molecule into 2