5 - Drug Metabolism Flashcards
Why would you want a drug to be lipophilic or water soluble?
Lipophilic - in order to access tissues (therapeutic effect)
Water soluble - so it can be retained in the blood and excreted
What are the two stages of drug metabolism?
Phase 1 - Adding a reactive group to increase polarity
Phase 2 - Adding a water soluble conjugate onto the reactive site
What are the possible Phase 1 reactions?
Oxidation (creating) - [most common, starts with hydroxylation] electrophiles, R=0 R-O-R [triangle]
Hydrolysis/reduction (unmasking) - nucleophiles, R-OH R-SH R-NH2
Where are most Phase 1 reactions carried out?
In the liver, by the cytochrome P450 enzymes (SER of hepatocytes)
There are 57 subtypes of P450.
What is aspirin converted to in Phase 1?
Salicylic acid (hydrolysis unmasking)
What is nicotine converted to in Phase 1?
Cotinine (oxidation)
What is cocaine converted to in Phase 1?
Ecgonine Methyl Ester + Benzoic Acid (hydrolysis)
What is chloral hydrate converted to in Phase 1?
Trichloroethanol (reduction)
What can Phase 1 metabolites be?
Inert
Active e.g. cannabis, prolongs effects
Active (from prodrug) e.g. codeine to morphine
What are the possible Phase 2 reactions?
For oxidation:
glutathione conjugation R-SG, glutathione, electrophiles
For hydrolysis/reduction
glucuronidation R-GI, UDP-glucuronic acid, OH NH2 SH COOH
acetylation R-Ac, Acetyl CoA, OH NH2
sulfation R-SO2H, 3’ phosphoadenosine 5’ phosphoadenosine, OH NH2
Which is the most common Phase 2 reaction?
Glucuronidation
Describe glucuronidation and sulfation in terms of their affinity and capacity?
Glucuronidation is low affinity/high capacity - more likely to occur at high drug doses e.g. aspirin
Sulfation is high affinity/low capacity e.g. low dose paracetamol
Explain the basis of paracetamol overdose
Paracetamol is first metabolised via sulfation.
As more paracetamol is taken glucuronidation is used (low affinity/high capacity)
However, electrophile and subsequent glutathione conjugates are very reactive.
Paracetamol, NAPQI , conjugate
When overdosing, the glutathione stores are depleted and NAPQI begins to build up. NAPQI is highly toxic.
Name some other less common Phase 2 pathways
Acetylation (aromatic amines), N-acetyl transferase (NAT enzyme), Acetyl CoA e.g. Isoniazid
Methylation, methyltransferases e.g. Levodopa
Amino acid conjugation, react with carboxylic acid or amine group of amino acid
Why is drug metabolism so important?
Biological half-life is decreased
Duration of exposure is reduced
Accumulation of the compound in the body is avoided
Potency/duration of the biological activity of the chemical can be altered
The pharmacology/toxicology of the drug can be governed by its metabolism
