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James MedChem Lecture (Powerpoint 1) Flashcards

1
Q

What is the fate of a drug taken orally? (5 steps)

A
  1. Drug dissolves from its dosage form
  2. Drug is absorbed from the intestinal tract
  3. Drug distributes to the tissues of the body (including the site of action)
  4. Drug may be converted to metabolites
  5. Drug and its metabolites are eliminated
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2
Q

What is James’ definition of metabolism?

A

The entire fate of a drug in the body, or the conversion of a drug into a metabolite

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3
Q

What is James’ definition of biotransformation?

A

The conversion of a drug to a metabolite

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4
Q

What is the definition of Xenobiotic?

A

Used to describe small organic molecules that are not used by the body for nutrition or normal physiological functions
(Includes therapeutic drugs, herbal remedies, food additives, preservatives, pesticides, pollutant chemicals, some natural products, other small organic molecules)

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5
Q

By definition, the process of biotransformation alters the ____________ of a drug molecule. This is quite likely to alter the __________ of the drug. It may also change the _________ of the drug.

A
  • Chemical structure
  • Desired biological (pharmacological) activity of the drug
  • Toxicity
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6
Q

The process of biotransformation almost always results in the formation of a more __________ metabolite, which means it will be more…

A
  • Water-soluble

- Readily secreted from the body

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7
Q

The rate and extent of biotransformation of a drug will determine the __________ of the drug.

A

Duration of action

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8
Q

Drugs are often designed to be lipophilic. Why?

A

Because they are most effective when taken orally. They are able to cross the plasma membrane.

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9
Q

Lipophilic drugs are converted to ________ by enzymes. Why?

A

They are converted to hydrophilic molecules so they stay inside the cell when they enter across the plasma membrane.

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10
Q

What do Phase 1 reactions do?

A

Introduce or uncover functional groups

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11
Q

What are other names for Phase 1 reactions? (2)

A

Non-synthetic or functionalization reactions

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12
Q

What do Phase 2 reactions do?

A

An endogenous, usually water-soluble, small molecule combines with a functional group on the drug or its phase 1 metabolite

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13
Q

What are other names for Phase 2 reactions? (2)

A

Synthetic or conjugation reactions

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14
Q

True or False: There always has to be a Phase 1 reaction before a Phase 2 reaction can ocur

A

False.

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15
Q

What are the 3 major Phase 1 reactions?

A

Oxidation, Hydrolysis, Reduction

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16
Q

What are the major Phase 2 reactions?

A

Glucuronidation, Sulfonation, Acetylation, Amino Acid conjugation, Glutathione conjugation

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17
Q

What are the “other” Phase 2 reactions?

A

Methylation, fatty acid conjugation, cholesterol conjugation

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18
Q

The first metabolite formed from a drug (also called the parent drug) is called a ____________

A

Primary metabolite

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19
Q

A metabolite formed from a primary metabolite is called a ___________

A

Secondary metabolite

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20
Q

Enzymes of drug biotransformation generally have ______ substrate selectivity

A

Broad

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21
Q

Why is it advantageous for biotransformation enzymes to have broad substrate selectivity?

A

Because the body already has enzymes that can metabolize (biotransform) new drugs that are introduced by the pharmaceutical industry

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22
Q

What 5 enzymes listed catalyze oxidation reactions?

A 
Cytochrome P450 (CYP)
Flavin monooxygenase (FMO)
Alcohol and aldehyde dehydrogenase
Monoamine oxidase
Xanthine oxidase
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23
Q

Each individual CYP has a unique _________ and _______.

A

Primary amino acid structure; Overall protein structure

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24
Q

All CYP’s have a ________ that is essential for activity

A

Heme-iron group (heme prosthetic group)

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25
CYP are ________-bound enzymes in humans and animals, found in the ___________ of the cell.
Membrane-bound | Endoplasmic reticulum
26
What enzyme is required for electron transfer in CYP-catalyzed reactions?
NADPH-cytochrome P450 reductase
27
NADPH supplies how many electrons?
2
28
What ultimately happens in the CYP-cycle? (How is the final product different?)
A hydrogen is removed and replaced with a hydroxyl group
29
What does CYP do to aromatic rings?
Aromatic hydroxylation (adds a hydroxyl group)
30
What does CYP do to aliphatic chains? (ie R-CH2-CH3)
- Aliphatic hydroxylation (adds a hydroxyl group) or - Desaturation (forms double bonds)
31
What does CYP do to secondary or tertiary amines?
N-dealkylation (removes one of the alkyl groups) or N-Oxidation (adds an oxygen or oxygen group)
32
What does CYP do to ethers?
O-dealkylation (removes one of the alkyl groups)
33
What does CYP do to sulfides?
S-Oxidation (adds an oxygen or oxygen group)
34
What does CYP do to double bonds?
Epoxidation (forms an epoxide ring)
35
What does CYP do to alkyl halides?
De-halogenation (removes the halogen)
36
What other things are required in CYP catalyzed dehalogenation?
Reductase, NADPH, molecular oxygen
37
What is the final product in CYP catalyzed dehalogenation? (how is the product different?)
The halogen is removed and the carbon becomes a carboxylic acid (the H is replaced with hydroxyl group, hydroxyl group is oxidized, the chlorine group is replaced with a hydroxyl group)
38
In R-(+)-warfarin, which position in the benzene ring gets hydroxylated predominantly?
the 6 position
39
In S-(+)-warfarin, which position in the benzene ring gets hydroxylated predominantly?
the 7 position
40
CYP is a versatile _________
mono-oxygenase
41
CYP can catalize oxygenation at _, _, or _ atoms in a drug
C, N, S
42
Flavin monooxygenase catalyzes oxidation of _, _, and _ atoms in organic molecules
P, N, S
43
What does flavin monooxygenase require to catalyze a reaction?
Cofactor NADPH and molecular oxygen
44
What do alcohol and aldehyde dehydrogenases require to catalyze reactions?
Oxygen and NADH or NADPH
45
What is the final product in an alcohol dehydrogenase catalyzed reaction?
Turns alcohol into a carbonyl group (it becomes an aldehyde)
46
What is the final product in an aldehyde dehydrogenase reaction?
The aldehyde becomes a carboxylic acid
47
What do monoamine oxidases require to catalyze reactions?
Oxygen and NADH
48
What is the final product in a monoamine oxidase catalyzed reaction?
The amine is released as ammonia and replaced with a carbonyl group (C-N bond becomes C=O) OR the N is oxidized to imine (double bonded N)
49
What does xanthine oxidase require to catalyze reactions?
Oxygen and NADH
50
What does xanthine oxidase do?
Removes double bonds and forms carbonyl groups in their place
51
The amide bond is often (more/less) stable to hydrolysis than the ester bond
More
52
What do ester hydrolases do?
Hydrolyze esters, they turn them into carboxylic acids and release the R group
53
What do amidases do?
Turn amides into amino groups and release the R group
54
_________ are often more substrate-selective than other esterase-amidase enzymes
Peptidase
55
Peptidase is a type of ________.
amidase
56
What enzyme catalyzes hydrolysis of epoxides?
Epoxide hydrolase
57
Where does reduction usually occur?
Lower gastrointestinal tract (bacteria and mucosa)
58
What is required for reduction to occur?
NADPH
59
What is Azo reduction?
Reduction of double bonded nitrogens to amino groups | splits the molecule into two
60
The most common phase 1 reactions are...
Oxidation and hydrolysis
61
CYPs account for what percentage of phase 1 reactions in drug biotransformation?
75-80%
62
Esterases and epoxide hydrolases account for what percentage of phase 1 reactions in drug biotransformation?
5-10%

Medicinal Chemistry (6 decks)

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