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Drug Metabolism Flashcards

1
Q

What is the main purpose of drug metabolism?

A

detoxification
inactivation
activating prodrugs
providing active/more active metabolites

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2
Q

What is the best way to eliminate the drug?

A

increase water solubility

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3
Q

What are the reactions of phase 1 metabolism?

A

oxidation
reduction
hydrolysis

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4
Q

Phase 2 metabolism reactions?

A

glucuronic acid conjugation
sulfate conjugation
amino acid conjugation
glutathione conjugation
methylation and acetylation

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5
Q

Methylation and acetylation generally terminate drug action but do not increase?

A

water solubility

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6
Q

Are drugs lipid or water soluble?

A

lipid

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7
Q

The liver, intestines, and other metabolic sites will perform how many transformation to eliminate a drug?

A

the minimum number

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8
Q

Functional groups are more likely to undergo metabolic transformation if they are?

A

easily accessible and are not sterically hindered

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9
Q

Most oxidative transformations are catalyzed by what kind of enzymes?

A

CYP450
flavin monooxygenase
alcohol dehydrogenase
aldehyde dehydrogenase

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10
Q

Oxidation

A

loss of electrons, hydrogen, alkyl group, or a heteroatom
gain of oxygen

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11
Q

in CYP450 oxidation the carbon atom that is oxidized must contain what?

A

a hydrogen atom that can be abstracted

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12
Q

CYP450 mechanism

A
  1. drug attaches to Fe^3+
  2. complex is reduced
  3. oxygen is added
  4. auto oxidation forms a radical
  5. complex is reduced
  6. loss of water
  7. hydrogen abstraction and carbon radical formed
  8. radicals combine to form oxidized drug and release iron
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13
Q

What are the 6 major cyp enzymes that are required for metabolism of endogenous substances?

A

CYP7
CYP11
CYP17
CYP19
CYP21
CYP27

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14
Q

If a drug induces a CYP enzyme, it leads to an increase in ?

A

drug metabolism

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15
Q

If a drug inhibits a CYP enzyme, it leads to a decrease in?

A

[drug]

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16
Q

What major CYP enzymes are involved in xenobiotic metabolism?

A

CYP1
CYP2
CYP3

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17
Q

Flavin monooxygenase enzymes

A

directly oxidize N and S
do not require an H atom on the N or S

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18
Q

Where are unsubstituted phenyl rings primarily oxidized and why?

A

para position
lack of steric hinderance

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19
Q

Which enhances aromatic hydroxylation: EWG or EDG?

A

EDG

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20
Q

Alkene oxidation produces ?

A

epoxides, trans diols, and peroxides

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21
Q

Alkene oxidation needs at least one of which atom?

A

H

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22
Q

Benzylic oxidation

A

oxidation occurs at the least sterically hindered site
benzylic carbon atom directly attached to an aromatic ring
does not usually occur with C-hydroxyl/ether bonds
can sometimes make toxic isomers

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23
Q

Allylic oxidation

A

carbon atom must have a hydrogen attached to it
occurs at carbon attached to an alkene

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24
Q

Where does oxidation of aliphatic and alicyclic carbon atoms occur?

A

at the terminal methyl group in the chain or the penultimate carbon atom in the chain

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25
Q

What are the 3 major oxidative transformations for amines and amides?

A

oxidative deamination
oxidative N-dealkylation
N-oxidation

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26
Q

Quaternary nitrogen atoms can undergo?

A

only N-dealkylation

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27
Q

Oxidative deamination

A

complex is oxidized to form a carbinolamine
carbinolamine is then delaminated o form a ketone and amine
primarily occurs with primary amines, sometimes secondary amines

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28
Q

Oxidative N-dealkylation

A

secondary or tertiary amine is oxidized into a carbinolamine
this is deaminated into a primary amine and a ketone or aldehyde
NOT for t-butyl

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29
Q

N-oxidation

A

direct oxidation of the nitrogen atom
primary route of oxidative metabolism for aromatic nitrogen

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30
Q

Primary amines can be directly oxidized to form?

A

hydroxylamines, imines, oximines, ,aldehydes, and carboxylic acids

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31
Q

Secondary amines can be directly oxidized to form?

A

hydroxylamines, imines, nitrogen, aldehydes, and carboxylic acid

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32
Q

Tertiary amines and heterocyclic amines can be directly oxidized to form?

A

N-oxides

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33
Q

Which functional group is most likely to undergo N-oxidation into N-oxides?

A

Heterocyclic Amines

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34
Q

Alcohol Dehydrogenase

A

enzymes that catalyze the oxidation of primary and secondary hydroxyl groups to aldehydes and ketones

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35
Q

Aldehyde Dehydrogenase

A

enzymes that catalyze the oxidation of aldehydes to carboxylic acids

36
Q

What is the intermediate in oxygen dealkylation? Is it stable?

A

hemiacetal or hemiketal
no

37
Q

Thioesters can undergo direct S-oxidation with FMO to produce?

A

sulfoxides
sulfones

38
Q

Desulfuration

A

thiocarbonyl -> carbonyl
oxidation

39
Q

Can oxidative dehalogenation remove halogens from aromatic rings?

A

no, need a hydrogen atom

40
Q

reduction

A

gain of hydrogen
least common pathway

41
Q

Aldehydes are primarily oxidized to?

A

carboxylic acids

42
Q

When ketones are reduced what sometimes forms?

A

a chiral center

43
Q

Azo groups can be reduced to ?

A

2 aromatic amines

44
Q

Nitro groups can be reduced to ?

A

primary amines

45
Q

Sulfoxides are normally oxidized to sulfones but can sometimes be reduced to ?

46
Q

Hydrolysis

A

breaking water bonds
occurs with esters, amides, lactones, lactams, phosphate esters, sulfonylureas, carbamates, and glycosides
phase 1 metabolic transformation
way to activate prodrug

47
Q

prodrug

A

compound that is either inactive/ possess weak activity and requires in vivo metabolism to convert to the active metabolite
activated by hydrolysis

48
Q

Advantages of prodrugs

A

enhanced water solubility for concentrated IV/ ophthalmic solutions
enhanced lipid solubility
enhanced duration of action
decreased side effects
selective activation at site of actio n

49
Q

What does each conjugation pathway use?

A

transferase enzyme

50
Q

Conjugation with what enhances water solubility and generally results in inactive products?

A

glucuronic acid
sulfate
amino acid

51
Q

Glutathione

A

react is with highly electrophilic intermediates
detoxifies drug molecules
highly water soluble, readily excreted, non toxic

52
Q

Addition of which groups terminate pharmacological actions of drug molecules?

A

methyl and acetyl groups

53
Q

All phase 2 conjugation paths except for what require an initial activation process?

A

glutathione

54
Q

Which phase 2 reaction cannot be reversed?

A

glutathione

55
Q

Why are aromatic rings not hydroxylated?

A

halogens, EWGs deactivate hydroxylation

56
Q

Amides can undergo what 2 reactions?

A

N-dealkylation and N-oxidation

57
Q

S-dealkylation of a thioether makes?

A

a thiol and an aldehyde

58
Q

Oxidative Dehalogenation product possibilities

A

aldehyde
ketone
call halide
carboxylic acid

59
Q

Oxidation of Alicyclic amines

A
  1. N-dealkylation
  2. Ring opens
    3.Oxidation
  3. condensation
60
Q

Disulfide bonds can be reduced to?

A

Thiol metabolites

61
Q

Where are hydrolytic enzymes?

A

liver, GI tract, plasma, skin, lungs, and kidneys

62
Q

Which occurs faster: hydrolysis of of esters and lactose or amides and lactams?

A

esters and lactose

63
Q

Which transferase and deconjugating enzymes are used in glucuronic acid conjugation?

A

UDP-Glucuronyl Transferase (UGT)
Beta-glucuronidase

64
Q

Which transferase and deconjugating enzymes are used in sulfate conjugation?

A

Sulfotransferase (SULT)
Sulfatase

65
Q

Which transferase and deconjugating enzymes are used in amino acid conjugation?

A

N-Acyltransferase
Amidase

66
Q

Which transferase and deconjugating enzymes are used in glutathione conjugation?

A

Glutathione S-transferase
NO DECONJUGATION

67
Q

Which transferase and deconjugating enzymes are used in acetylation?

A

N-acetyltransferase (NAT)
Amidase

68
Q

Which transferase and deconjugating enzymes are used in methylation?

A

methyltransferase
CYP450 oxidative phosphorylation

69
Q

Why is glucuronic acid conjugation the most common Phase 2 transformation?

A

acid is readily available; is an oxidative metabolite of glucose
can conjugate a large number of functional groups

70
Q

Which functional groups can glucuronic acids conjugate?

A

hydroxyl groups— most common
phenols—most common
carboxylic acids
tetrazoles
amines
sulfonamides
hydrazines
carbamates
sulfhydryl groups

71
Q

Due to the stereochemistry of alpha-glucose 1-phosphate and the mechanism of the transferase reaction, glucuronic acid always forms a?

A

Beta glucuronic

72
Q

Adding glucuronic acid to a drug increases what kind of solubility?

73
Q

Sulfate conjugation occurs with which functional groups?

A

mainly: phenolic hydroxyl groups
minor: aliphatic hydroxyl groups, aromatic amines, and N-hydroxyl groups

74
Q

Which enzyme releases estrogen at its tissue?

75
Q

Sulfate conjugation make make minor products that are?

A

highly reactive and cytotoxic

76
Q

Amino acid conjugation adds what?

A

carboxylic acids

77
Q

Which amino acids are used in amino acid conjugation?

A

mainly: Gly and Gln
minor: Aspartic acid, Serine, and Taurine

78
Q

Amino acid conjugation is primarily linked to which functional groups?

A

aromatic carboxylic acids
aryl acetic carboxylic acids

79
Q

Is the carboxylic acid activated before or after amino acid conjugation?

80
Q

Adding Gly or Gln during amino acid conjugation enhances what kind of solubility?

81
Q

What does glutathione conjugation protect the body from?

A

potentially harmful electrophiles

82
Q

What is glutathione?

A

a tripeptide made of gamma-glutamate, cysteine, and glycine

83
Q

Glutathione conjugation process

A
  1. initial conjugation
  2. removal of gamma-Glu and Gly
  3. N-acetylation
84
Q

Acetylation

A

pathway that uses Acetyl CoA to acetylate primary aliphatic amines, primary aromatic amines, hydrazines, hydrazine’s, and unsubstituted sulfonamides

does NOT produce a more water soluble metabolite

85
Q

Methylation

A

helps make nuclei acids, proteins, phospholipids, neurotransmitters, and other amines
seen with catechols, phenolic hydroxyl groups, amines, and sulfhydryl groups

DOES NOT ENHANCE WATER SOLUBILITY
inactivates drug molecules

86
Q

Where does methylation of catechols normally occur?

A

meta position

87
Q

methyltransferase enzymes

A

catechol-O-methyltransferase
phenol-O-methyltransferase
N-methyltransferase
S-methyltransferase

Pharmacology (16 decks)

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