Pharmacology 5 - Drug Metabolism Flashcards
Why would you want a drug to be lipophilic?
So the drug can access tissues and have a therapeutic effect
Why would you want a drug to be water soluble?
So it can be retained in the blood and delivered to excretion sites
How does the body alter drugs, compared to how they are designed?
- Drugs are designed as relatively lipid soluble (non-polar to enter blood)
- The body then alters the drug to make it water soluble and easier to excrete
- The body converts drugs to metabolites
What are the two kinds of biochemical reaction involved in drug metabolism?
- Phase 1: introduce a reactive group to the drug to increase polarity
- Phase 2: add a water soluble conjugate to the reactive group, making it easier to excrete
Describe the process of phase 1 metabolism of drugs
- Hydrolysis unmasks new functional groups, while oxidation creates new functional groups (most common with hydroxylation first)
- Result is electrophiles (oxidation) or nucleophiles (reduction)
- The functional group can then serve as a point of attachment for phase 1 reactions
- Uses cytochrome P450 enzymes (57 types)
Describe what happens in phase 2 metabolism
Functional groups are conjugated, making them more polar to improve excretion
What is sulfation in phase two metabolism?
- High affinity/low capacity
- Most likely to happen at low drug dosages
What is the most common pathway of phase 2 metabolism?
- Glucuronidation
- Low affinity/high capacity therefore more likely to happen at high dosages
What is glutathione conjugation?
- A form of phase 2 metabolism pathway
- The drug needs to be electrophilic to be conjugated or biotransformed to an electrophilic conjugate
What is the problem with phase 2 metabolism?
- Electrophiles are very reactive
- Paracetamol overdose results in glutathione stores being overwhelmed, so NAPQI damages the liver
List the phase 2 metabolism pathways
- Sulfation
- Glucaronidation
- Glutatione conjugation (glutathione targets elecrophiles)
- Acetylation (acetyl coA - usually aromatic amine)
- Methylation
- Amino acid conjugation (carboxylic acid group or amino acid group)
What is the importance of drug metabolism?
- Biological half life of drug is reduced
- Duration of exposure is reduced
- Accumulation of the compound in the body is avoided
- Potency/duration of biological activity of the chemical can be altered
- Pharmacology/ toxicology of the drug can be governed by its metabolism
How is aspirin changed in phase 1 metabolism ?
Oxidation to salicylic acid - converts ester group to hydroxyl group
What are the possible pathways in phase 1 metabolism?
- Active parent drug to inert metabolite (no effect on body)
- Active parent drug can form an active metabolite (has effect on the body and prolongs effects)
- Inactive parent drug can be produced to an active metabolite (prodrug, eg. codeine)
Describe the phase 2 metabolism of aspirin
- Glucuronidation (glucaronide)
- Replaces OH group in salicylic acid
How is paracetemol metabolised (phase 2)?
- Sulfation (40-60%) /glucuronidation (20-30%)
- Glutathone conjugation 10%(paracetamol to NAPQI - highly reactive, will react with glutathione)
Describe the structure of glutathione and what it reacts with
- A tripeptide consisting on cysteine, glutamic acid and glycine
- Reacts with electrophiles such as NAPQI
What is paracetamol used as?
- An analgesic (pain relief)
- And anti-pyretic (reduces redness)
Describe the phase 1 metabolism of paracetamol
Converted to NAPQI, a highly electrophilic intermediate, via cytochrome P450 enzymes (mainly present in the smooth endoplasmic reticulum)
What is required for sulfation of paracetamol?
- Sulphotransferase enzyme
- PAPS co-substrate
What is required for glucoronidation of paracetamol?
- UDP-glucuronosyltransferase
- UDP-glucoronic acid co-substrate
How does glucoronidation of NADPQI occur?
- GSH attacks the electrophilic carbon (as it is a nucleophile)
- Aided by the enzyme glutathione S-transferase
What is administered in the case of paracetamol overdose?
- A drug is given that allows glutathione to be synthesised
- N-acetyl cysteine is used, oral or IV
- Oral methionine can also be used, a highly reactive nucleophile
- These reduce the use of the sulphation pathway and may also reduce NAPQI
Which metabolites of paracetamol would you expect to find in the bile, urine and serum?
- Bile - Large molecular weight therefore glucaronide and glutathione conjugates
- Urine - sulphate conjugates, glucaronide, mecapturate and parent drug
- Serum - parent drug
