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LIFE207 > Phase I Metabolism (CYP450) > Flashcards

Phase I Metabolism (CYP450) Flashcards

1
Q

What is the purpose of Phase I Metabolism?

A

To functionalise typically lipophilic molecules for Phase II Metabolism by introducing or revealing functional groups that increase polarity.

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2
Q

What chemical reactions are involved?

A

Oxidation (most common), reduction, and hydrolysis.

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3
Q

Oxidation involves…

A

loss of electrons by the reactant (the drug being metabolised).

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4
Q

Reduction involves…

A

gain of electrons by the reactant (the drug being metabolised).

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5
Q

Hydrolysis involves…

A

the addition of a water molecule to another large molecule (the drug being metabolised), in order to break the latter down into multiple smaller molecules (the ensuing metabolites).

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6
Q

What are the three possible outcomes of Phase I metabolism?

A
  1. The drug metabolite is rendered completely pharmacologically inactive.
  2. The drug metabolite retains some level of pharmacological activity, though this would be lower than that of the drug prior to its being metabolised).
  3. The original substance taken in (prodrug) isn’t pharmacologically active, and one of its metabolites is.
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7
Q

What characterises metabolites post-Phase I Metabolism?

A

Small decrease in lipophilicity
Small increase in excretion
No change in pharmacological effect

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8
Q

A common Phase I oxidation…

A

involves the conversion of a C-H bond to a C-OH bond. This sometimes converts a pharmacologically inactive compound (prodrug) to a pharmacologically active one.

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9
Q

The dangers of Phase I Metabolism…

A

It’s also capable of ‘turning’ nontoxic drug molecules into poisonous ones (process referred to as toxification).

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10
Q

What is an example of toxification via Phase I Metabolism?

A

Conversion of acetonitrile to HOCH2CN, which rapidly dissociates into formaldehyde and hydrogen cyanide.

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11
Q

Where on CYP450 enzymes do drugs bind?

A

Apoprotein

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12
Q

What determines which drug can bind to what CYP450 enzyme?

A

Ultimately the sequence of the apoprotein, which differs between each CYP450 enzyme

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13
Q

What is the prosthetic group common to any and all CYP450 enzymes?

A

Ferritoprotoporphyrin IX (Fe3+ iron molecule)

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14
Q

CYP450 enzyme cycle

A

Substrate binds (to active site on the apoprotein of CYP450) -> e- transferred from NADPH to CYP450 (by CYP450 reductase) -> reduces Fe3+ to Fe2+ in prosthetic group -> one oxygen (from molecular oxygen) binds to now reduced Fe2+ on prosthetic group -> transferred to substrate -> product is released and replaced by a molecule of water

molecule of water from the other oxygen binding to two protons.

alt. where molecular oxygen binds to substrate after CYP450 reduced, where it accepts a second electron to form an intermediate (?)

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15
Q

What are the cofactors for P450-mediated oxidations?

A

[O] and NADPH

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16
Q

What is aliphatic hydroxylation?

A

Hydroxyl group (-OH) is introduced into the substrate at aliphatic carbon atoms. Occurs at secondary or tertiary sites.

Target: methyl groups
Cofactors: [O], NADPH
R-CH3 -> R-CH2-OH

17
Q

Which drugs undergo aliphatic hydroxylation as part of Phase I metabolism?

A

Tolbutamide - hypoglycaemic agent in diabetes treatment
Ibuprofen - analgesic, antipyretic
Nevirapine - antiretroviral (HIV)

18
Q

What is aromatic hydroxylation?

A

Hydroxyl group (-OH) is introduced into the substrate at aromatic carbon atoms.

Target: benzene ring
Cofactors: [O], NADPH
benzene-OH

19
Q

Which drugs undergo aromatic hydroxylation as part of Phase I metabolism?

A

Salicylic acid - psoriasis, analgesic
Metabolite: gentisic acid (excreted via kidney)

Warfarin - anticoagulant (rat poison)

20
Q

What is an epoxidation reaction?

A

Phase I Metabolism where the oxygen for epoxidation is derived from molecular oxygen.

Epoxide metabolites frequently cause drug toxicity (covalently bind proteins).

Target: benzene ring
Cofactors: [O], NADPH

21
Q

What drugs typically undergo epoxidation as part of Phase I metabolism?

A

Carbamazepine - anticonvulsant (used to treat epilepsy)
Metabolite: carbamazepine epoxide

Benzoapyrene (found in cigarette smoke)

22
Q

What kind of dealkylations are there?

A

O- and N-dealkylation

23
Q

What is O-dealkylation as part of Phase I metabolism?

A

Involves the removal of protecting groups in order to unmask hydroxyl functions (pre-existing) on the substrate.

Target: ether
Cofactors: [O], NADPH
Product: alcohol
Byproduct: formaldehyde
R-O-CH3 -> R-OH + HCHO

24
Q

What drugs undergo O-dealkylation as part of their Phase I metabolism?

A

Phenacetin - analgesic, related to paracetamol (prodrug)
Metabolite: paracetamol

Codeine - opiate (recreational)
Metabolite: morphine

25
Q

What is N-dealkylation as part of Phase I metabolism?

A

Removal of an N-alkyl group (N-alkyl = nitrogen-containing alkyl side chain… an N-alkyl is …N-CH3)

Target: tertiary amine
Cofactors: [O], NADPH
Product: amine
Byproduct: formaldehyde

26
Q

What drugs undergo N-dealkylation as part of their Phase I Metabolism?

A

Diazepam - anxiety, alcohol withdrawal
Metabolite: nordiazepam

If levels of both accumulate - toxicity, side effects: sedation, slurred speech, ataxia

27
Q

What is deamination?

A

Removal of an amino group (NH2) from the drug.

Target: -NH2
Cofactors: [O], NADPH
Product: ketone
Byproduct: NH3 (ammonia)

28
Q

Which drugs undergo deamination as part of their Phase I Metabolism?

A

Amphetamine - used to treat ADHD or narcolepsy, now recreational
Metabolite: Phenylacetone (inactive)

Sertraline - antidepressant
Metabolite: sertraline ketone

29
Q

What is N-oxidation?

A

The oxidation of an N-atom in a substrate, typically by the addition of an O atom into the molecule.

Target: secondary amine
Cofactors: [O], NADPH
Product: hydroxylamine

Hydroxylamines produce methemoglobin (iron is in Fe3+ state, not Fe2+ state so cannot bind oxygen)

30
Q

Which drugs undergo N-oxidation as part of Phase I metabolism?

A

Clozapine
Metabolite: Clozapine N-oxide

31
Q

What is S-oxidation?

A

S-atom is oxidised by incorporating an O atom into the S-containing group.

R-S-R

Target: Sulphide
Cofactors: [O], NADPH
Byproduct: sulphoxide

32
Q

What is alcohol oxidation?

A

Converting an alcohol into an aldehyde.

Target: alcohol
Cofactors: [O], NADPH
Product: acetaldehyde
Byproduct: water

33
Q

Which drugs undergo alcohol oxidation?

A

Ethanol
Metabolite: Acetaldehyde

34
Q

What is dehydrogenation?

A

Removal of H atoms from a substrate.

Target: aminophenol
Cofactors: [O], NADPH
Product: quinonimine
Byproduct: water

35
Q

Which drugs undergo dehydrogenation as part of their Phase I Metabolism?

A

Paracetamol
Metabolite: NAPQI (N-acetyl-p-benzoquinoneimine) Toxic, produced in small amounts (normally) and immediately detoxified in the liver

36
Q

What is dehalogenation?

A

(Quite rare) Cleavage of carbon-hydrogen bonds

Target: haloalkane
Cofactors: [O], NADPH
Product: alkane

37
Q

Which drugs undergo dehalogenation?

A

Halothanes (volatile inhalation anaesthetics)
Metabolite: trifluoroacetic acid

LIFE207 (3 decks)

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