Properties of Metabolites Flashcards
What are the exceptions to most metabolites being inert?
- Pharmacologically active metabolites
- Reactive metabolites
- Metabolites than contribute to DDIs (enzymes and transporter interaction)
Examples of drugs that produce pharmacologically active metabolites?
Mainly phase I - clopidogrel, diazepam
Some phase II - ezetemibe, morphine
Examples of drugs that produce reactive metabolites?
Paracetamol (overdose)
Example of drug where metabolites contributes to DDIs?
Gemfibrozil
What determines the importance of a pharmacologically active metabolite?
- affinity for receptor - may be comparable to the parent molecule
- plasma concentration of the metabolite
What processes are critical when establishing significance of pharmacologically active metabolites?
formation of the metabolite, and elimination of it
the balance of the two determines the exposure of the metabolite to the body
Metabolism of diazepam - the three products?
- Nordiazepam (M1) - N-demethylation
- Temazepam (M2) - hydroxylation
- sequential metabolism to form a common product of both (M3) - oxazepam (which then undergoes glucuronidation)
Which diazepam metabolites are pharmacologically active?
All 3
Which diazepam metabolite is the most significant?
M1 (nordiazepam) - the other two are very rapidly metabolised and not detectable in plasma
Clinical uses of M2 and M3 metabolites of diazpeam?
Temazepam and oxazepam respectively - marketed as short acting alternatives to diazepam
What are reactive metabolites?
Short half life, react quickly.
result in local toxicity (at formation site)
What can prevent toxicity of reactive metabolites?
Conjugation with glutathione
Examples of reactive metabolite forming compounds?
Benzopyrene- a major molecule in cigarette smoke. forms reactive metabolites in the lungs
Paracetamol - causes liver failure in overdose
What is the balance between toxication and detoxication pathways?
- molecules form either a stable or reactive metabolite
- stable metabolites eliminated as inert material
- reactive metabolites either protected (glutathione) or are too unstable to eliminate and cause toxicity
What type of molecule is glutathione?
Nucleophile and tripeptide
reacts with phase 1 metabolites and provides very important protective mechanism
Substitute for glutathione in paracetamol overdose?
N-acetyl cysteine
Time frame for administering N-acetyl cysteine after overdose?
ideally within 8 hours
Different toxic responses possible from drugs?
- developmental damage (teratogenesis)
- antigenic conjugate (immune response)
- tissue damage (necrosis)
- DNA damage (mutation, cancer)
What are the types of ADR?
A B C D
What are type A ADRs?
Reversible adverse responses
split into A1 (pharmacological related action) and A2 (effects unrelated to drug action)
What is significant of type B C and D ADRs?
There are irreversible and toxic - not related to specific enzymes/transporters, non selective effects and reactive metabolites are often implicated
What are Type B ADRs?
- idiosyncratic and non predictable
- often have a genetic basis (metabolite binds to protein and recognised as antigen)
- e.g. Carbemazepeine induced Stephen-Johnsons Syndrome
- commonly associated with liver
What are Type C ADRs?
- toxicity from chemical reaction between drug/metabolite and tissue macromolecules
- often leads to cell death (necrosis)
- liver is particularly prone to this
- e.g. paracetamol toxicity
What are Type D ADRs?
chronic toxicity - similar mechanism to B and C
What are the types of Type D toxicities?
- teratogenic
- mutagenic
- carcinogenic
Thalidomide example of teratogenic effects?
- caused severe birth defects in babies
- forms reactive metabolites that affect human development
- rats were resistant to the teratogenicity
What is the FDA guidance on testing metabolites?
- less polar and >25% of parent AUC
- more polar and >100% of parent AUC
