Elementary Drug Metabolism

Question 1

Main features of Phase 1 drug metabolism

Answer 1

Change in the drug by oxidation, reduction or hydrolysis

Oxidation:
- accomplished by cytochrome P450 enzymes
- can produce harmful metabolites
- drug molecule incorporates one atom of O2 to the drug to form a hydroxyl group

Reduction:
- Cytoplasmic enzymes metabolise drugs

Hydrolytic reactions:
- Ester and amide bonds susceptible to hydrolysis

Question 2

Main features of Phase 2 drug metabolism

Answer 2

Conjugation - The combination of a drug with one of several polar molecules to form a water-soluble metabolite

Glucuronidation

Features:
- Terminates all biological activity
- Occurs in the liver
- Products excreted via kidneys

Question 3

What is bioavailability and its equation?

Answer 3

The amount of drug that eventually reaches systemic circulation of an administered dose of the drug for that route of administration.

F = Quantity of drug reaching systematic circulation / Quantity of drug administered

Route of administration can effect bioavailability

Question 4

The monooxygenase P450 cycle

Answer 4

1. Drug enters cycle as drug substrate, RH
2. Molecular oxygen provides two atoms of oxygen
3. One atom of oxygen is added to the drug to yield the hydroxyl product, ROH, which leaves the cycle, the second oxygen combines with protons to form H2O

Question 5

What is Glucuronidation?

Answer 5

Reaction involving the transfer of glucuronic acid to electron-rich atoms of the substrate

Involved enzyme: Uridine diphosphate-glucuronosyltransferases

Co-factor: Uridine diphosphate-glucuronic

Question 6

Paracetamol and the liver

Answer 6

Normal dose: Paracetamol is metabolised to a glucuonate and a sulphate (phase 2 reactions)

Overdose: These processes are saturated and P450 mixed function oxidases to produce a toxic metabolite - NAPBQI