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Mpharm 1 > PH1125 - Drug metabolism > Flashcards

PH1125 - Drug metabolism Flashcards

1
Q

Why is drug metabolism important?

A

recognises potential toxicities, optimisation of prodrugs and prediction of half life.

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2
Q

What are CYP monooxygenases?

A

Major catalyst of endogenous compounds oxidised in the liver, lungs, kidneys and GI.

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3
Q

what is a pro-drug?

A
  • a biologically inactive compound that can be metabolized in the body to produce a drug
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4
Q

what is absorption?

A
  • transfer of drug from the site of administration to blood
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5
Q

what is distribution?

A
  • (reversible) transfer of drug from one PK compartment to another
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6
Q

what is metabolism?

A
  • chemical conversion of compounds (biotransformation)
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7
Q

what is excretion?

A
  • removal of drug from the body without chemical alteration
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8
Q

what is elimination?

A
  • metabolism and excretion
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9
Q

why are CYP 450 enzymes called that?

A
  • carbon monoxide binds to the reduced Fe(II) haem and absorbs at 450nm
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10
Q

where are CYPs found?

A
  • they are in smooth endoplasmic reticulum (SER) in close association with NADPH-CYP reductase
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11
Q

What are CYP reactions essential for?

A

production of many things like steroids eg. cholesterol.

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12
Q

How do CYP enzymes work?

A

catalyse oxidation reactions by changing C-H to C=O group. By radical intermediates.

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13
Q

what does the reductase do in oxidative reactions?

A
  • serves as the electron source
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14
Q

what is an example of CYP mediated biotransformations where there is a formation of an active metabolite?

A
  • codeine to morphine
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15
Q

what is an example of CYP mediated biotransformations where there is a formation of an inactive metabolite?

A

phenobarbital to hydroxyphenobarbital

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16
Q

what is an example of CYP mediated biotransformations where there is a formation of a toxic metabolite?

A
  • paracetamol to NAPQI
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17
Q

what processes does paracetamol undergo to form NAPQI? (2)

A
  • N-hydroxylation
  • rearrangement

(mediated by CYP)

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18
Q

how many metabolites are produced for most drugs? (2)

A
  • less than 10 major metabolites

- possibly several minor metabolites

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19
Q

what are the problems with metabolites?

A
  • they can accumulate and cause toxicity
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20
Q

what is phase I metabolism?

A
  • chemically diverse small molecules are converted and transformed into generally more polar compounds
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21
Q

what are the phase I CYP reactions? (5)

A
  • hydroxylation (aliphatic and aromatic)
  • epoxidation
  • dealkylation (N-, O-, S-)
  • deamination
  • oxidation (N-, S-)
22
Q

what are the phase I non-CYP reactions? (2)

A
  • oxidation

- hydrolysis

23
Q

when a racemic mixture of warfarin is administered which isomer produces the anticoagulant response?

A
  • S-warfarin
24
Q

why is the S-warfarin the active form of warfarin? (2)

A
  • S-warfarin has 1 major site of metabolism whereas R-warfarin has 3
  • when there are more major site of metabolism it is broken down quicker and less efficient
25
Q

what does the rate of second substitution depend on?

A
  • the substrate
26
Q

How can you slow down the rate of aromatic hydroxylation?

A

substitute phenol ring with a para-chlorine group (deactivate the ring).

27
Q

What enzyme is used to catalyse codeine to morphine?

A

CYP2D6.

28
Q

what effects the rate of aromatic hydroxylation?

A
  • the more electron rich an electron ring the faster the rate of aromatic hydroxylation
29
Q

what is a common approach to slow down or block aromatic hydroxylation?

A
  • substitute phenyl ring with a para-fluorine or para-chlorine which deactivates the ring
30
Q

what happens in oxidative N-dealkylation?

A
  • C-H → C-OH → NH + C=O
31
Q

what happens in oxidative O-dealkylation?

A
  • C-H → C-OH → OH + C=O
32
Q

what are poor metabolizers?

A
  • people deficient in CYP2D6 and thus no activity
33
Q

what does morphine undergo after its conversion from codeine?

A
  • glucuronidation
34
Q

for non-cyp oxidation what is MAO? (3)

A
  • monoamine oxidase (in mitochondria)
  • oxidatively deaminates endogenous neurotransmitters (eg dopamine)
  • some drugs are designed to inhibit MAO used to affect balance of CNS neurotransmitters
35
Q

for non-cyp oxidation what is FMO? (3)

A
  • flavin monooxygenases

- family of enzymes that catalyse oxygenation of nitrogen, phosphorous, sulphur

36
Q

for non-cyp oxidation what is xanthine oxidase? (2)

A
  • allopurinol is a substrate for xanthine oxidase

- used for treatment of gout

37
Q

what is an example of non-cyp hydrolysis? (2)

A
  • ester hydrolysis (ester to carboxylic acid)

- pethidine metabolized by liver carboxyesterase to form carboxylic acid metabolite (no analgesic activity)

38
Q

which is more chemically stable (longer half life) an ester or amine? (2)

A
  • amine functional group is very stable and has a longer half life
  • ester linkage readily undergoes ester hydrolysis
39
Q

what happens in phase II metabolism?

A
  • conjugation which results in more polar compounds being formed and are rapidly eliminated into urine and/or bile
40
Q

what reactions do phase II metabolism include? (5)

A
  • glucuronidation
  • sulphation
  • amino acids
  • acetylation
  • methylation
41
Q

what enzyme does glucuronidation need?

A
  • UDP-Glucuronosyl-Transferase (UDPGT)
42
Q

what groups are conjugated in glucuronidation? (6)

A
  • OH
  • COOH
  • NH2
  • NR2
  • SH
  • CH
43
Q

what happens in glucuronidation? (2)

A
  • links the drug to still more polar molecules to render them even more easy to excrete
  • adds C6H9O6
44
Q

what happens in acetylation? (2)

A
  • OH turns to C=O

- NH2 turns to NH

45
Q

what is the solubility of sulphotranferase and where are they found? (2)

A
  • they are soluble

- found in cell cytoplasms

46
Q

what does the drug act as in sulphation?

A
  • nucleophile (R-OH drug)
47
Q

what are the two metabolites of paracetamol and their percentages? (2)

A
  • paracetamol-glucuronide (60%)

- paracetamol-sulphate (35%)

48
Q

what is the other 5% of paracetamol metabolised to?

A
  • NAPQI
49
Q

what happens to NAPQI during phase II metabolism and why? (3)

A
  • glutathione conjugation
  • prevents toxicity of oxidative metabolites after normal doses
  • this mechanism is swamped after an overdose
50
Q

what happens in a paracetamol overdose? (4)

A
  • more paracetamol is shunted to the cytochrome P450 system to produce NAPQI
  • hepatocellular stores of glutathione become depleted
  • NAPQI reacts with cellular membrane molecules (including proteins and nucleic acids)
  • resulting in hepatocyte damage and death

Mpharm 1 (59 decks)

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