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Foundations I > Intro to Drug Metabolism & Phase I Metabolism > Flashcards

Intro to Drug Metabolism & Phase I Metabolism Flashcards

1
Q

Why are some drugs/xenobiotics metabolized?

A

It’s a defense mechanism
- To increase water solubility of hydrophobic molecules for excretion
- To protect against all types of “reactive” molecules

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2
Q

Where are drugs/xenobiotics metabolized?

A

In the liver
- gets absorbed in the gut and does the first-pass right after which has an impact on oral F (decreases the fraction that gets through)
- Every subsequent pass – CLH (metabolism of a portion of drug molecules in systemic circulation occurs on every pass back through the liver)

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3
Q

How are drugs/xenobiotics metabolized?

A

Phase I enzymes & Phase II enzymes

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4
Q

Two general sets of enzyme-catalyzed reactions

A

– Phase I enzymes: introduce or expose polar groups
– Phase II enzymes: “synthetic” – form conjugates

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5
Q

What affects the rates of drug/xenobiotic metabolism?

A
  1. Enzyme expression levels (when enzyme expression increases, the rate of clearance will increase because you have more enzyme that catalyzes the reaction)
  2. Inhibition (if you bind something to the enzyme and inhibit it, clearance decreases)
  3. Genetic polymorphisms/variability
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6
Q

The balanced molecular properties that drugs need:

A
  • aqueous solubility high enough to dissolve in the
    gut to drive absorption and to reach concentrations high enough to saturate receptor in tissues
  • hydrophobic enough to diffuse across membranes
    and, in many cases, to enhance binding affinity to receptor
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7
Q

A drug is excreted unchanged via

A

kidney

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8
Q

What does it mean when a drug is metabolized?

A

chemical structures and properties are changed through enzyme-catalyzed reactions

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9
Q

These drugs may be excreted primarily
unchanged:

A

Polar and ionic drugs

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10
Q

Hydrophobic drugs are metabolized to become

A

polar, ionic and more water soluble

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11
Q

Orally delivered drugs are subject to both

A

prehepatic metabolism in the gut and more
extensive first-pass metabolism in the liver that
lowers bioavailability.

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12
Q

Two types of Enzyme-Catalyzed Reactions

A
  1. Primarily Xenobiotic
  2. Primarily Endobiotic
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13
Q

Primarily Xenobiotic

A

not expected to be in body

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14
Q

Primarily Endobiotic

A

synthesized in body

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15
Q

Phase I Class of Drug Metabolizing Enzymes

A

Introduce or Expose Polar Groups

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16
Q

Phase II Class of Drug Metabolizing Enzymes

A

Use “activated cofactors” to form drug-conjugates

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17
Q

Phase I Groups

A

Oxidation
Oxidation/Reduction
Hydrolysis/Hydration

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18
Q

Phase II Groups

A

Nucleophile in Drug
Electrophile in Drug

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19
Q

Oxidation

A
  1. Cytochrome P450 (CYP)
  2. Flavin Monooxygenase (FMO)
    - Require NADPH + O2
    - reveal a nucleophile: a Phase I Rxn
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20
Q

Oxidation/Reduction

A
  1. Alcohol Dehydrogenase (ADH)/Carbonyl Reductase (CBR)
  2. Aldehyde Dehydrogenase (ALDH)
    - Require NAD+/NADH
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21
Q

Hydrolysis/Hydration

A
  1. Esterase (CES)
  2. Amidase
  3. Epoxide Hydrolase (EH)
    - Reactions with H2O
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22
Q

Nucleophile in Drug

A

Glucuronosyl Transferase (UGT)
Sulfotransferase (SULT)
N-Acetyl Transferase (NAT)

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23
Q

Electrophile in Drug

A

Glutathione S-Transferase (GST)

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24
Q

CYPs

A
  • aliphatic C-H -> C-OH
  • N-, O-, S-dealkylation
  • dehalogenation
  • aromatic C-H -> C-OH
  • epoxidation C=C
  • N-H -> N-OH
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25
Q

CYPs & FMOs

A

N-, S-oxidation

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26
Q

ADH & ALDH

A
  • R2CHOH –> R2C=O
  • aldehyde oxidation RCH=O -> RCO2H
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27
Q

Esterase
Amidase

A
  • ester hydrolysis
  • amide hydrolysis
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28
Q

Epoxide hydrolase

A

epoxide hydration

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29
Q
  • glucuronides – UGTs
  • sulfates – SULTs
  • peptide conjugates – N-acyl-amino acid transferases
A

Form conjugates to increase water solubility

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30
Q
  • N-acetylation – NATs
  • methylation – methyl transferases
A

Form conjugates to decrease nucleophilic reactivity

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31
Q

glutathione conjugates – GSTs

A

Form conjugates to eliminate reactivity and increase water solubility

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32
Q

Each drug may be metabolized via

A

one or more single or multi-step pathways

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33
Q

Which enzyme(s) are responsible for ”clearance” of a given drug depends on

A

the chemical structure of the drug

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34
Q

Common Path of Metabolism for Hydrophobic Drugs

A
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35
Q

nucleophile

A
  • a chemical species or an atom within a molecule that has a tendency to donate a pair of electrons to another atom
  • their electron-rich nature allows them to seek out and react with electron-deficient species
  • Examples include negatively charged ions like hydroxide ions (OH-), chloride ions (Cl-), and cyanide ions (CN-)
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36
Q

Phase I reactions increase

A

water solubility to some extent

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37
Q

Phase II anionic conjugates dramatically increase

A

water solubility and lead to excretion

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38
Q

Predominant pathways for first metabolites depend on

A

key structural features

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39
Q

Phase I oxidations (CYP reactions) dominate in

A

the absence of polar nucleophiles

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40
Q

Phase II conjugations (UGT) dominate if

A

polar nucleophile present

41
Q

Various outcomes from
these biotransformations

A
  • active drug –> active metabolite
  • active drug –> inactive metabolite
  • active drug –> reactive “metabolite”
  • inactive (prodrug) –> active metabolite (“drug”)
42
Q

Pharmacologically inactive prodrugs become activated by

A

one of the drug metabolizing enzymes

43
Q

The most common prodrug design utilizes

A

esters that are hydrolyzed to active acids or alcohols

44
Q

Genetic polymorphisms/variability

A

presence of different versions of a gene or DNA sequence within a population, resulting in genetic diversity among individuals.
- may lower kcat –> lower rate
- may increase km –> lower rate
- may have opposite effect on km or kcat –> higher rate
- may have gene copies –> more total energy, higher rate

45
Q

Rates are directly proportional to

A

Enzyme expression levels

46
Q

Rates can be affected by

A

inhibitors of the drug-metabolizing enzymes

47
Q

Rates in different individuals may vary because of

A

genetic
polymorphisms

48
Q

Polar and ionic drugs may be excreted primarily

A

unchanged

49
Q

Hydrophobic drugs are more extensively

A

metabolized

50
Q

Phase I reactions primarily introduce or “expose” nucleophiles that are then subject to

A

Phase II conjugation reactions

51
Q

Phase II reactions form conjugates of drug nucleophiles or electrophiles with groups that

A
  • eliminate that reactivity
  • increase the size of the conjugate
  • introduce a low pKa anionic group that significantly increases water solubility
52
Q

Enzymes catalyzing major initial transformations of parent drugs in the liver are key to

A
  • clearance of drug
  • potential drug-drug interactions
  • variability in patient response
53
Q

Orally delivered drugs are subject to both

A
  • prehepatic metabolism in the gut
  • more extensive first-pass metabolism in the liver
54
Q

Biotransformations may convert

A
  • active drugs into inactive metabolites
  • active metabolites
  • reactive metabolites that can lead to various types of toxicities
55
Q

Absorption

A

Hydrophilic enough to dissolve in the gut

56
Q

Distribution

A

Hydrophobic enough to diffuse across cell membranes

57
Q

Metabolism

A
  • increase water solubility of hydrophobic drugs to be excreted
  • Protect against reactive molecules
  • where: Liver (majority), gut, lungs
  • how: first-pass metabolism, Phase I and Phase II reactions
58
Q

Excretion

A

urine and/or feces
- Polar/ionic drugs mainly excreted unchanged by the kidney
- Metabolized drugs become more water soluble for entry into tubule lumen ⇨ urine

59
Q

First-Pass Metabolism

A

Fraction of orally delivered drugs are subject to both pre-hepatic metabolism in the gut and more extensive first-pass metabolism in the liver which decreases bioavailability (F) before reaching systemic circulation

60
Q

If you want to increase the bioavailability (F) of a drug substantially, what can you do?

A

Give the drug IV

61
Q

What leads to the pk differences in IV vs oral administration?

A

IV avoids first-pass CYP enzymes in gut/liver, 100% enters systemic circulation

62
Q

The fraction of oral drug that is absorbed and escapes both gut and liver first-pass metabolism ultimately becomes the fraction
that

A

is fully available for your body to use, aka F < 1.

63
Q

Some drugs are administered as Prodrugs that become activated by

A

first-pass metabolism

64
Q

Enzyme catalyzed reactions that introduce or expose

A

polar groups

65
Q

Oxidation

A
  • Require NADPH + O2
  • CYPs and FMOs
66
Q

Oxidation/Reduction

A
  • Require NAD+/NADH
  • ADH/CBR, ALDH
67
Q

Hydrolysis

A
  • Reactions with H2O
  • Esterase, Amidase, Epoxide Hydrolase
68
Q

Phase I Metabolism

A
  • Increase water solubility to some extent
  • Dominate in absence of polar nucleophiles
69
Q

Phase II Metabolism

A
  • Increase water solubility dramatically and lead to excretion (urine/feces)
  • Dominate if polar nucleophile is present
70
Q

In Phase II Metabolism, enzyme catalyzed reactions use

A

activated cofactors to form drug conjugates

71
Q

Nucleophile in drug

A
  • Form conjugates to increase water solubility (UGTs, SULTs, N-acyl-amino acid transferases)
  • Form conjugates to decrease nucleophilic activity (NATs, methyl transferases)
72
Q

Electrophile in drug

A

For conjugates to eliminate reactivity and
increase water solubility (GSTs)

73
Q

Prodrugs and Possible Pathways

A
  • active drug –> active metabolite
  • active drug –> inactive metabolite
  • active drug –> reactive metabolite
74
Q

What are some factors that can affect the rate of a reaction and efficacy of the drug?

A
  • enzyme levels
  • enzyme inhibitors (DDIs)
  • genetic polymorphisms
  • enzyme saturation
75
Q

Reactions that come from CYP enzymes

A
  1. Aliphatic hydroxylation
  2. N-H Hydroxylation
  3. Epoxidation
  4. Aromatic Hydroxylation
  5. N-Oxidation
  6. O-dealkylation
  7. N-dealkylation
  8. Dehalogenation
76
Q

N-dealkylation

A
77
Q

N-Oxidation

A
  • O is added
78
Q

Dehalogenation

A
79
Q

N-H Hydroxylation

A
  • you add an alcohol group
80
Q

Aliphatic hydroxylation

A

hydroxyl group

81
Q

O-dealkylation

A

methyl group is being removed

82
Q

Aromatic

A
83
Q

Epoxidation

A
84
Q

What are the major CYP families that are
involved in ~90% of drug/xenobiotic metabolism?

A
  • CYP 1A
  • CYP 2C/D/E
  • CYP 3A
85
Q

Which subfamilies have the highest 3 proportions of drug metabolism?

A
  • CYP 3A4/5
  • 2D6
  • 2C9
86
Q

Amidases

A
87
Q

Esterases

A
88
Q

ADH- alcohol dehydrogenase

A
89
Q

ALDH - aldehyde dehydrogenase

A
90
Q

EH - epoxide hydrolase

A
91
Q

Carbonyl reductase

A
92
Q

ADH/CBR are

A

REVERSIBLE redox reactions of alcohols to
aldehydes/ketones (and vice versa)

93
Q

Why do we need to remove aldehydes?

A

Aldehydes can react to amines on proteins and modify their function

94
Q

Which drug do we use to treat alcohol abuse?

A

Disulfiram. By inhibiting ALDH we increase the buildup of aldehyde leading to bad SE.

95
Q

Does 1st pass metabolism affect a drug’s clearance?

A

No! First pass metabolism affects the bioavailability (F) of the drug prior to it reaching systemic circulation. Since clearance is defined by the removal of parent drug from the body once it has been in systemic circulation, first pass metabolism would not be included

96
Q

Phase I Reactions expose/introduce polar groups, revealing nucleophiles making the drug MORE

A

water soluble, and can lead to EASIER excretion.

97
Q

If a drug is ANIONIC it will most likely need

A

TRANSPORTERS (and is usually highly water soluble!)
- Phase I rxns increase water solubility LESS than Phase II rxns

98
Q

From a Phase I reactions, drugs can either

A

be completely eliminated or further metabolized by Phase II enzymes/rxns

Foundations I (14 decks)

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