Lecture 19 : Drub Metabolism and Excretion (started going downhill from around here)

Question 1

What is drug elimination

Answer 1

Irreversible removal of the drug from the body

Can be done by :
- Excretion of unchanged drug
- Metabolism (biotransformation, liver)
- Usually metabolised then the materials are excreted

Question 2

What is metabolism and how is it done

Answer 2

Done by enzymes, mostly in liver.

Most common way…

Phase 1 (modification) :
- Cytochrome P450-dependent oxidase (contains haem group, a P450 is a GROUP of enzymes, not a specific one)
- Causes oxidation, reduction or hydrolysis
- Forming highly reactive compounds

Phase 2 (conjugation) :
- Joins metabolite to another molecule to give it a charge (aids excretion)
- Glutathone (GSH), sulfate, glycine or glucuronic acid

Question 3

Prodrugs

Answer 3

Converted from an inactive drug to an active drug when metabolised

Question 4

Paracetamol metabolism pathway

Answer 4

Phase 1 :
- P450 (either CYP2E1, 1A2 or 2D6) N-hydroxylyses paracetamol forming NAPQI

Phase 2 :
- Conjugated to glutathione

When overdosed on, conjugation cannot proceed quick enough and NAPQI accumulates, causing liver damage

Question 5

Routes for drugs and metabolites that are excreted / eliminated :

Answer 5

1. Renal, by filtration in glomerulus, secretion in proximal tube
2. Hepatic / biliary, so faecal or enterohepatic elimination (metabolite -> bile -> shat)
3. Sweat, body milk, breath (Evaporated at lungs)

Question 6

How does drug elimination in the kidney work

Answer 6

• 20% of plasma filtered in glomerlus, where charged / polar molecules are ‘trapped in tubules so lost in urine
• If drugs secreted by same transporter, they compete and so slow their excretion
• Urine tends to be acidic so ion trapping can be mediated by pH
• Some drugs actively secreted into tubules by 2 families of transporters : Acid transporters (for penicinillin), or organic base transporters (for pethidine, quinine)

Question 7

Regular Bolus Dosing

Answer 7