ADME 3 and 4

Question 1

What are the sites of drug metabolism?

Answer 1

Main site=Liver

Others: -GI Tract -Intestinal wall

        - Plasma(acetylsalicylate=converts aspirin to salicylate)
        - Specialised tissues- monoamine oxidases in nerve endings(eg noradrenaline⇒adrenaline)

Question 2

What does drug metabolism result in?

Answer 2

Drug⇒More H2O soluble metabolite(non-polar)

1. Less likely to diffuse into cells to reach receptors
2. Favours increased excretion in urine or bile
3. Usually abolishes activity and terminates drug action BUT

• Can promote activity-prodrug eg acetylsalicylate, zidovudine
• No change in activity eg diazepam
• Produce toxic metabolites eg paracetamol

Question 3

What are the two drug metabolism reactions?

Answer 3

Phase 1= addition or uncovering of a reactive group

Phase 2= conjugation of an endogenous molecule with drug

Question 4

What does the phase 1 reaction involve and what is the purpose for this?

Answer 4

Phase 1 involves

• Oxidation
• Reduction
• Hydrolysis

These reactions make the molecule more susceptible for the phase 2 reactions

Question 5

What does the phase 2 reaction involve and what effect does this have?

Answer 5

Phase 2 reaction involves

• Glucoronide
• Sulphate
• Amino acids, GSH
• Acetylation and Methylation

This makes the molecules more polar(water soluble)= ideal substrates for active transport and excretion

Question 6

What is the most important reaction for phase 1 metabolism of drugs?

Answer 6

Oxidation

Question 7

What enzymes are involved in oxidation(metabolism of drugs)?

Answer 7

1. Cytochrome P450- located on the smooth endoplasmic reticulum
2. Closely related isoenzymes(CYP1,CYP2 and CYP3) encode enzymes involved in drug metabolism.
3. ⇒These enzymes require O2, NADPH and cytochrome P450 reductase.

Question 8

What are the factors that influence drug metabolism?

Answer 8

1. Organ function-liver, kidney, heart, gut
2. Diseases-uptake of other drugs
3. Diet, cigarettes, alcohol
4. Age, sex
5. Pregnancy