3 Phases

Provide a functional group (e.g. OH or NH 2 ) to: increase polarity of the drug provide a site for phase II reactions

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)

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

a)Monoamine oxidases b)Hypochrome P600 enzymes c)Cytochrome P450 enzymes d)Hypochrome P450 enzymes e)Cytochrome P600 enzymes

1.Molecular oxygen 2.NADPH (an electron donor) 3.NADPH cytochrome P450 reductase

Cytochrome P450 enzyme system mature and… 1.Relative liver mass higher 2.Relative hepatic blood flow higher

CYP2D6 converts the pro-drug codeine to the active drug morphine CYP2D6 is absent in 7% of caucasians

a)Orange juice b)Apple juice c)Coca Cola d)Beetroot juice e)Grapefruit juice

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

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

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

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

1.Paracetamol normally undergoes phase II reaction 2.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

4. Initially the toxic metabolite NAPBQI is inactivated by glutathione 5. Glutathione later becomes depleted and there is increased cell death What could you give someone suffering from paracetamol overdose?

4. Initially the toxic metabolite NAPBQI is inactivated by glutathione 5. 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)