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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
What are the 3 major oxidative transformations for amines and amides?
oxidative deamination oxidative N-dealkylation N-oxidation
26
Quaternary nitrogen atoms can undergo?
only N-dealkylation
27
Oxidative deamination
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
28
Oxidative N-dealkylation
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
29
N-oxidation
direct oxidation of the nitrogen atom primary route of oxidative metabolism for aromatic nitrogen
30
Primary amines can be directly oxidized to form?
hydroxylamines, imines, oximines, ,aldehydes, and carboxylic acids
31
Secondary amines can be directly oxidized to form?
hydroxylamines, imines, nitrogen, aldehydes, and carboxylic acid
32
Tertiary amines and heterocyclic amines can be directly oxidized to form?
N-oxides
33
Which functional group is most likely to undergo N-oxidation into N-oxides?
Heterocyclic Amines
34
Alcohol Dehydrogenase
enzymes that catalyze the oxidation of primary and secondary hydroxyl groups to aldehydes and ketones
35
Aldehyde Dehydrogenase
enzymes that catalyze the oxidation of aldehydes to carboxylic acids
36
What is the intermediate in oxygen dealkylation? Is it stable?
hemiacetal or hemiketal no
37
Thioesters can undergo direct S-oxidation with FMO to produce?
sulfoxides sulfones
38
Desulfuration
thiocarbonyl -> carbonyl oxidation
39
Can oxidative dehalogenation remove halogens from aromatic rings?
no, need a hydrogen atom
40
reduction
gain of hydrogen least common pathway
41
Aldehydes are primarily oxidized to?
carboxylic acids
42
When ketones are reduced what sometimes forms?
a chiral center
43
Azo groups can be reduced to ?
2 aromatic amines
44
Nitro groups can be reduced to ?
primary amines
45
Sulfoxides are normally oxidized to sulfones but can sometimes be reduced to ?
sulfides
46
Hydrolysis
breaking water bonds occurs with esters, amides, lactones, lactams, phosphate esters, sulfonylureas, carbamates, and glycosides phase 1 metabolic transformation way to activate prodrug
47
prodrug
compound that is either inactive/ possess weak activity and requires in vivo metabolism to convert to the active metabolite activated by hydrolysis
48
Advantages of prodrugs
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
What does each conjugation pathway use?
transferase enzyme
50
Conjugation with what enhances water solubility and generally results in inactive products?
glucuronic acid sulfate amino acid
51
Glutathione
react is with highly electrophilic intermediates detoxifies drug molecules highly water soluble, readily excreted, non toxic
52
Addition of which groups terminate pharmacological actions of drug molecules?
methyl and acetyl groups
53
All phase 2 conjugation paths except for what require an initial activation process?
glutathione
54
Which phase 2 reaction cannot be reversed?
glutathione
55
Why are aromatic rings not hydroxylated?
halogens, EWGs deactivate hydroxylation
56
Amides can undergo what 2 reactions?
N-dealkylation and N-oxidation
57
S-dealkylation of a thioether makes?
a thiol and an aldehyde
58
Oxidative Dehalogenation product possibilities
aldehyde ketone call halide carboxylic acid
59
Oxidation of Alicyclic amines
1. N-dealkylation 2. Ring opens 3.Oxidation 4. condensation
60
Disulfide bonds can be reduced to?
Thiol metabolites
61
Where are hydrolytic enzymes?
liver, GI tract, plasma, skin, lungs, and kidneys
62
Which occurs faster: hydrolysis of of esters and lactose or amides and lactams?
esters and lactose
63
Which transferase and deconjugating enzymes are used in glucuronic acid conjugation?
UDP-Glucuronyl Transferase (UGT) Beta-glucuronidase
64
Which transferase and deconjugating enzymes are used in sulfate conjugation?
Sulfotransferase (SULT) Sulfatase
65
Which transferase and deconjugating enzymes are used in amino acid conjugation?
N-Acyltransferase Amidase
66
Which transferase and deconjugating enzymes are used in glutathione conjugation?
Glutathione S-transferase NO DECONJUGATION
67
Which transferase and deconjugating enzymes are used in acetylation?
N-acetyltransferase (NAT) Amidase
68
Which transferase and deconjugating enzymes are used in methylation?
methyltransferase CYP450 oxidative phosphorylation
69
Why is glucuronic acid conjugation the most common Phase 2 transformation?
acid is readily available; is an oxidative metabolite of glucose can conjugate a large number of functional groups
70
Which functional groups can glucuronic acids conjugate?
hydroxyl groups— most common phenols—most common carboxylic acids tetrazoles amines sulfonamides hydrazines carbamates sulfhydryl groups
71
Due to the stereochemistry of alpha-glucose 1-phosphate and the mechanism of the transferase reaction, glucuronic acid always forms a?
Beta glucuronic
72
Adding glucuronic acid to a drug increases what kind of solubility?
water
73
Sulfate conjugation occurs with which functional groups?
mainly: phenolic hydroxyl groups minor: aliphatic hydroxyl groups, aromatic amines, and N-hydroxyl groups
74
Which enzyme releases estrogen at its tissue?
sulfatase
75
Sulfate conjugation make make minor products that are?
highly reactive and cytotoxic
76
Amino acid conjugation adds what?
carboxylic acids
77
Which amino acids are used in amino acid conjugation?
mainly: Gly and Gln minor: Aspartic acid, Serine, and Taurine
78
Amino acid conjugation is primarily linked to which functional groups?
aromatic carboxylic acids aryl acetic carboxylic acids
79
Is the carboxylic acid activated before or after amino acid conjugation?
before
80
Adding Gly or Gln during amino acid conjugation enhances what kind of solubility?
water
81
What does glutathione conjugation protect the body from?
potentially harmful electrophiles
82
What is glutathione?
a tripeptide made of gamma-glutamate, cysteine, and glycine
83
Glutathione conjugation process
1. initial conjugation 2. removal of gamma-Glu and Gly 3. N-acetylation
84
Acetylation
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
Methylation
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
Where does methylation of catechols normally occur?
meta position
87
methyltransferase enzymes
catechol-O-methyltransferase phenol-O-methyltransferase N-methyltransferase S-methyltransferase

Pharmacology (16 decks)

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