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PED2001 - Drug Disposition > Non Cyp Phase 1 > Flashcards

Non Cyp Phase 1 Flashcards

1
Q

What enzymes cause oxidation reactions

A

Flavin linked monooxygenases (FMO)
Prostaglandin H synthase dependent co oxidation
Amine oxidase
Oxidoreductase

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2
Q

What enzymes cause hydrolysis

A

Esterases
Epoxide hydrolases

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3
Q

Where are FMOs found

A

ER

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4
Q

What do FMOs oxidise

A

Nucleophilic N, P or S centres

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5
Q

What does FMO require

A

NADPH, O2 and FAD prosthetic group

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6
Q

FMO reaction mechanism

A
  1. NADPH reduces FAD —> FADH2
  2. O2 binds NAPD+-FADH2 complex
  3. Forms FADH-OOH
  4. Reacts with nucleophile substrate
  5. One O is incorporated into substrate and the other into water
  6. H2O and NADP+ is released
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7
Q

How many isoforms of FMO is there

A

5 - show 50-55% identity with each other

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8
Q

Give 2 examples of FMO catalysed reactions

A

N-deacetyl ketaconozole —> N-deacetyl-N-hydroxyketaconozole

Tamoxifen —> Tamoxifen-N-oxide

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9
Q

Which FMO is found at high levels in the human liver

A

FMO3

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10
Q

Which FMO is found in the human kidney

A

FMO1

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11
Q

Which FMO is found in rat liver

A

FMO1

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12
Q

Which FMOs are found in rat kidney

A

FMO1 FMO3 FMO4

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13
Q

Explain the co-oxidation quality of PGHS

A

COX activity (arachidonic acid —> PGG2)
Peroxidase activity (PGG2 —> PGH2)

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14
Q

What is PGHS’s role in paracetamol overdose

A

High doses of paracetamol can be converted to the toxic N-acetylquinoneimime in the kidney

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15
Q

What do amine oxidases oxidise

A

Monoamine
Diamines
Polyamines

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16
Q

What do MAOs

A

Metabolise neurotransmitters via FAD-dependent pathway

17
Q

Which MAO metabolises propranolol

A

MAOA

18
Q

Where are amine oxidases found

A

Mitochondria

19
Q

Describe metabolism of dopamine

A

DA -MOA-> X -ald dehydrogenase-> HVA

20
Q

4 oxidoreductases

A

Alcohol dehydrogenase
Aldehyde dehydrogenase
Carbonyl reductase
NAD(P)H quinone oxidoreductase

21
Q

What are oxidoreductases dependent on

A

NADP in the oxidising direction
NADPH in the reducing direction

22
Q

Where are oxidoreductases found

A

Cytosol

23
Q

What is the “normal” method of ethanol detoxification

A

Alcohol dehydrogenase
(CYP2E1 used excess ethanol as a substrate)

24
Q

Ethanol metabolism pathway

A

Ethanol -ADH-> acetaldehyde -AlDH-> carboxylic acid

25
Q

What plays a role in cyclophosphamide metabolism

A

Aldehyde dehydrogenase
GSTs
Alcohol dehydrogenase
CYP2C9
CYP3A4

26
Q

What do carbonyl reductases do

A

Reduces quinones, prostaglandins, menadione

27
Q

Specific substrate of carbonyl reductase

A

Doxorubicin to doxorubicinol

28
Q

Why are quinone oxidoreductases important

A

Reduce quinones directly to hydroquinones without semiquinone intermediate by using 2 electrons instead of 1
- avoids generation of singlet oxygen

29
Q

Where are esterases found

A

Plasma and liver
Cytosolic and microsomal forms

30
Q

4 types of esterase

A

Butyrylcholinesterase
Carboxylesterase 1
Carboxylesterase 2
Paraoxonase

31
Q

What does cholinesterase metabolise

A

Aspirin

32
Q

What does CES1 metabolise

A

Cocaine / heroin

33
Q

What does CES2 metabolise

A

Procaine

34
Q

What does paraoxonase metabolise

A

Statins

35
Q

What do CES1 and CES2 prefer

A

CES1 - small OH group, large acyl group
CES2 - larger OH group, small acyl group

36
Q

What do epoxide hydrolases do

A

Cleave epoxides in the presence of water

37
Q

Where are EPHs found

A

Cytosol and microsomes

38
Q

Epoxide hydrolase in benzoapyrene genotoxicity

A

BaP —(CYP1)—> B-epoxide —(EPH)—> B-diol —(CYP1)—> BPDE

39
Q

What does PON1 do

A

Protects LDL and HDL from lipid peroxidation

PED2001 - Drug Disposition (13 decks)

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