Drug Metabolism

Question 1

What is a xenobiotic?

Answer 1

Foreign substance to the body like plant metabolites, drugs, intoxicants, food additives, industrial chemicals etc.

Question 2

What type of xenobiotic is easier to excrete from the system?

Answer 2

Water soluble xenobiotics - the lipophilic ones have to be conjugated by another compound - making them hydrophilic - before they can be excreted

Question 3

What occurs in phase 1 liver activation?

Answer 3

oxidation, reduction, and hydrolisation - essentially it conjugates the drugs to make them more easily excreted (from lipophilic to hydrophilic) -

Question 4

What is a potential danger with activating a xenobiotic in the liver?

Answer 4

We could potentially activate a drug that was previously not harmful - making it toxic when activated.

Question 5

Why do people have different reactions to drugs?

Answer 5

essentially because of genetic differences in P450 = which is a group of enzymes responsible for metabolism and detoxification of compounds after ingestion-
There is huge variability in the iso forms of P450 - there are also different inducers and inhibitors for each family of P450.

Question 6

Why might a variation in P450 lead to adverse drug reactions?

Answer 6

Because drugs may inhibit or agonise P450 activity causing adverse drug interactions.

Question 7

What is the risk of a Cytochrome P450 activator drug?

Answer 7

When the drug activates P450- it potentially reduces the effect of other drugs taken simultaneously by increasing the overall metabolic activity.

Question 8

What is the risk of Cytochrome P450 inhibiting drugs?

Answer 8

By inhibiting the cytochrome P450 you’re decreasing your metabolic activity in the liver - therefore you have more free/active drug substance in your body - could lead to an overdose of drug.

Question 9

What’s the relationship between drug metabolism and grapefruits?

Answer 9

Grapefruits are a Cytochrome P450 inhibitor - therefore they decrease the activity of this over time irreversibly = this has the potential to reduce your metabolism of drugs - therefore essentially leading to a drug overdose = too much free circulating drug

Question 10

What is the most common phase 1 reaction?

Answer 10

Oxidation - many oxidation reactions are catalysed by the mixed function oxidase system

Question 11

where does the hydroxylation reaction occur in the liver cell?

Answer 11

hydroxylation mainly takes place on the smooth endoplasmic reticulum of the liver cell -

Question 12

What is the mechanism of hydroxylation by the Cytochrome P450?

Answer 12

It takes molecular oxygen (O2) and it gives one to the substrate - then the other oxygen is reduced to water and eliminated

Question 13

Why are people native to East Asia more likely to not tolerate alcohol?

Answer 13

B/c they have a genetic aldehyde dehydrogenase deficiency - where acetaldehyde accumulates - symptoms include vasodilation, facial flushing and tachycardia -

Question 14

How is Disulfiram used to treat alcohol abuse?

Answer 14

helps to maintain your abstinence by accumulating in the fat tissue and irreversibly inhibits the oxidation of acetaldehyde by competing with NAD - this causes a 5-10 fold increase in acetaldehyde concentration producing unpleasant side effects when alcohol is introduced

Question 15

What reactions occur in the phase 2 reaction?

Answer 15

conjugations= add a functional group making the compound more polar = hydrophilic

These reactions may require energy to occur

Question 16

What phase 2 reaction is the most common?

Answer 16

Glucuronidation - most common and is used for drugs with OH, COOH and NH2 groups - it transfers a glucuronic acid group to the substrate by glucuronyl transferase

Question 17

What forms of drugs commonly undergo sulfation in phase two drug metabolism?

Answer 17

phenol drugs

Question 18

What forms of drugs commonly undergo glycine conjugation in phase two drug metabolism?

Answer 18

drugs with carboxyl groups

Question 19

What metabolite of paracetamol metabolism is toxic?

Answer 19

The secondary metabolite (NAPQI) which is toxic to the body and builds up in the liver and is highly reactive - normally it combines with glutathione - but when glutathione stores are depleted (in the case of paracetamol overdose) NAPQI combines with hepatic proteins and causes liver injury

Question 20

What are Polycyclic Aromatic Hydrocarbons?

Answer 20

They are benzene like rings which are incomplete combustion products (things like cigarettes, barbecued meat, exhaust fumes, oil and coal tar) they pass easily through cell membranes. During detoxification in the body, a reactive epoxide ring intermediate forms which can potentially block DNA replication-
associated with increase risk of cancer