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Drug Disposition > Properties of Metabolites > Flashcards

Properties of Metabolites Flashcards

1
Q

What are the exceptions to most metabolites being inert?

A
  • Pharmacologically active metabolites
  • Reactive metabolites
  • Metabolites than contribute to DDIs (enzymes and transporter interaction)
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2
Q

Examples of drugs that produce pharmacologically active metabolites?

A

Mainly phase I - clopidogrel, diazepam

Some phase II - ezetemibe, morphine

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3
Q

Examples of drugs that produce reactive metabolites?

A

Paracetamol (overdose)

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4
Q

Example of drug where metabolites contributes to DDIs?

A

Gemfibrozil

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5
Q

What determines the importance of a pharmacologically active metabolite?

A
  • affinity for receptor - may be comparable to the parent molecule
  • plasma concentration of the metabolite
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6
Q

What processes are critical when establishing significance of pharmacologically active metabolites?

A

formation of the metabolite, and elimination of it

the balance of the two determines the exposure of the metabolite to the body

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7
Q

Metabolism of diazepam - the three products?

A
  1. Nordiazepam (M1) - N-demethylation
  2. Temazepam (M2) - hydroxylation
  3. sequential metabolism to form a common product of both (M3) - oxazepam (which then undergoes glucuronidation)
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8
Q

Which diazepam metabolites are pharmacologically active?

A

All 3

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9
Q

Which diazepam metabolite is the most significant?

A

M1 (nordiazepam) - the other two are very rapidly metabolised and not detectable in plasma

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10
Q

Clinical uses of M2 and M3 metabolites of diazpeam?

A

Temazepam and oxazepam respectively - marketed as short acting alternatives to diazepam

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11
Q

What are reactive metabolites?

A

Short half life, react quickly.

result in local toxicity (at formation site)

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12
Q

What can prevent toxicity of reactive metabolites?

A

Conjugation with glutathione

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13
Q

Examples of reactive metabolite forming compounds?

A

Benzopyrene- a major molecule in cigarette smoke. forms reactive metabolites in the lungs
Paracetamol - causes liver failure in overdose

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14
Q

What is the balance between toxication and detoxication pathways?

A
  • 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
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15
Q

What type of molecule is glutathione?

A

Nucleophile and tripeptide

reacts with phase 1 metabolites and provides very important protective mechanism

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16
Q

Substitute for glutathione in paracetamol overdose?

A

N-acetyl cysteine

17
Q

Time frame for administering N-acetyl cysteine after overdose?

A

ideally within 8 hours

18
Q

Different toxic responses possible from drugs?

A
  • developmental damage (teratogenesis)
  • antigenic conjugate (immune response)
  • tissue damage (necrosis)
  • DNA damage (mutation, cancer)
19
Q

What are the types of ADR?

A

A B C D

20
Q

What are type A ADRs?

A

Reversible adverse responses

split into A1 (pharmacological related action) and A2 (effects unrelated to drug action)

21
Q

What is significant of type B C and D ADRs?

A

There are irreversible and toxic - not related to specific enzymes/transporters, non selective effects and reactive metabolites are often implicated

22
Q

What are Type B ADRs?

A
  • 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
23
Q

What are Type C ADRs?

A
  • 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
24
Q

What are Type D ADRs?

A

chronic toxicity - similar mechanism to B and C

25
Q

What are the types of Type D toxicities?

A
  • teratogenic
  • mutagenic
  • carcinogenic
26
Q

Thalidomide example of teratogenic effects?

A
  • caused severe birth defects in babies
  • forms reactive metabolites that affect human development
  • rats were resistant to the teratogenicity
27
Q

What is the FDA guidance on testing metabolites?

A
  • less polar and >25% of parent AUC

- more polar and >100% of parent AUC

Drug Disposition (11 decks)

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