Drug Metabolism Flashcards
Why would you want a drug to be lipophilic?
So drugs can access tissues by crossing the lipid membranes- therapeutic effect
Why would you want a drug to be water soluble?
So that it can be retained in the blood and delivered to excretion sites
What is the aim of drug metabolism?
Convert lipid-soluble drugs into less lipid-soluble (water-soluble) so that it is easier to excrete
What does the process of metabolism involve?
Conversion of drugs to metabolites
What two kinds of biochemical reactions does D.M involve?
Phase 1 - introduce a reactive group to the drug to increase polarity
Phase 2 - add a water-soluble conjugate to the reactive group
3 main reactions in Phase 1?
Oxidation - produce electrophile
Hydrolysis & reduction - produce nucleophile (-OH, -SH, -NH2)
Function of the 3 reactions in Phase 1?
Oxidation/reduction - adds new functional groups (serves at a point of attachment for phase II reactions)
Hydrolysis - unmasks the functional group
Main site and enzyme of drug metabolism in Phase 1?
The liver - cytochrome p450 (isoenzymes) on the SER
There are around 57 subtypes which metabolise different drugs
Most common Phase 1 metabolism?
Oxidation - often starts with hydroxylation (adding an hydroxyl group)
3 ways Phase 1 can work?
Active parent drug —> inert metabolite
e.g. nicotine and cocaine
Active parent drug —> active metabolite
prolongs effects as just another chemical carrying out these effects
Inactive parent drug —> active metabolite (prodrug)
e.g. codeine needs to be metabolised to morphine to work
4 different phase 2 reactions?
Glutathione conjugation
Glucuronidation
Acetylation
Sulfation
Phase 2 reaction for electrophiles?
Gluthathione conjugation
Conjugating agent = gluthathione
Phase 2 reaction for nucleophile (g)?
Glucuronidation
Conjugating agent = UDP-glucuronic acid
Target F.G = -OH, -COOH, -NH2, -SH
Phase 2 reaction for nucleophile (a)?
Acetylation
Conjugating agent = acetyl CoA
Target F.G = -OH & -NH2
Phase 2 reaction for nucleophile (s)?
Sulfation
Conjugating agent = 3’-phosphoadenosine-5’-phosphosulphate
Target F.G = -OH & -NH2
Most common Phase 2 metabolism?
Glucuronidation
Property of glucuronidation?
Has a low affinity/high capacity
SO more likely to occur at high drug dosages
Property of sulfation?
Has a high affinity/low capacity
SO more likely to occur at low drug dosages
E.g. of paracetamol and its dosages effects on Phase 2?
At low dosages, sulfation occurs
At higher dosages, switches to glucuronidation
Not all of paracetamol is metabolised by the main 2 methods - whats the 3rd method?
Glutathione conjugation
How do you convert paracetamol to an electrophile?
Generate NAPQI - change the hydroxyl group for a double-bond O to form an electrophile
Issue with glutathione conjugation?
Elecetrophiles are very reactive
If the gluthathione stores fall, high levels of reactive electrophile which can cause damage to liver, kidneys etc (happens when you OD)
Less common Phase 2 metabolism pathways?
Acetylation
Methylation
Aa conjugation
Importance of drug metabolism?
Biological half-life decreases
Duration of exposure reduced
Accumulation of compound in body avoided
Potency/duration of biological activity of chemical can be altered
Pharmacology/toxicology of drug can be governed by its metabolism
