Liver Metabolism of DrugsBy Aidan Cross and Tom Grant

How many phases of drug metabolism are there? (1 mark)

3 Phases

What is phase 1 of drug metabolism? (2)

Provide a functional group (e.g. OH or NH2)

to:• increase polarity of the drug• provide a site for phase II reactions

What is phase 2 of drug metabolism? (2)1. Conjugation (the attachment of a large

chemical group to a functional group on the drug molecule)

2. The resulting conjugate is normally more hydrophilic and inactive (thus more easily excreted from body)

What is phase 3 of drug metabolism? (2)

Transport into circulation or bile for elimination (renal vs faeces)

Which is the main enzyme groupinvolved in phase 1 drug metabolism? (1)

a) Monoamine oxidasesb) Hypochrome P600 enzymesc) Cytochrome P450 enzymesd) Hypochrome P450 enzymese) Cytochrome P600 enzymes

What does cytochrome P450 require to function? (3)

1. Molecular oxygen2. NADPH (an electron donor)3. NADPH cytochrome P450 reductase

Why might metabolism of drugs be fast in children? (1)

Cytochrome P450 enzyme system mature and…

1. Relative liver mass higher2. Relative hepatic blood flow higher

Why might a Caucasian patient not respond to codeine?

CYP2D6 converts the pro-drug codeine to the active drug morphine

CYP2D6 is absent in 7% of caucasians

What drink can inhibit drug metabolism?

a) Orange juiceb) Apple juicec) Coca Colad) Beetroot juicee) Grapefruit juice

Mr Jim has hypertension. He is on calcium channel blockers for this. He also has a history of depression and

is taking St John’s Wort. Why is this relevant? (2)

St John’s Wort induces CYP3A enzymes, so calcium channel blockers are more rapidly metabolised. Therefore the hypertension would be less effectively controlled.

What is bioavailability? (2)

The proportion of administered drug which reaches the systemic circulation unchanged and is thus available for distribution to the site of action.

What is first-pass metabolism?

Orally administered drugs that are metabolised in liver before they can reach circulation

*But note that with a lower first-pass metabolism, pro-drugs (such as ACE inhibitors) will be less effective

A chronic alcoholic staggers into your clinic. He smells of Malibu, pineapple juice and the little umbrella. Why might his

liver be less capable of metabolizing drugs? (2)

Predisposed to cirrhosis, therefore:

1. Dead and damaged hepatocytes decrease the drug-metabolizing capacity of the liver.

2. Porto-systemic shunting directs drugs away from the liver –> decreased first pass metabolism -> increased bioavailability

How can paracetamol overdose cause liver damage? (5)

1. Paracetamol normally undergoes phase II reaction2. In overdose, the conjugation pathway for phase II is saturated, so there is an

increase in phase I reactions.3. Phase I reaction produces toxic metabolite NAPBQI

Cont…

How can paracetamol overdose cause liver damage? (5)

4. Initially the toxic metabolite NAPBQI is inactivated by glutathione5. Glutathione later becomes depleted and there is increased cell death

What could you give someone suffering from paracetamol overdose?

How can paracetamol overdose cause liver damage? (5)

4. Initially the toxic metabolite NAPBQI is inactivated by glutathione5. Glutathione later becomes depleted and there is increased cell death

What could you give someone suffering from paracetamol overdose?

Acetylcysteine and methionine (because they increase synthesis of glutathione in liver)