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Medicinal Chemistry > Lecture 4 - Drug Metabolism > Flashcards

Lecture 4 - Drug Metabolism Flashcards

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1
Q

Why do drugs get metabolized?

A

The body needs a process to remove potentially harmful foreign chemicals (ex: drugs)

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2
Q

How can drugs be metabolized and which is the most important way?

A
  • Liver (most important)
  • Secretion into bile and elimination in feces
  • Kidneys elimination in urine
  • Lungs
  • Intestinal gut flora
  • Skin and other organs
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3
Q

What is first pass metabolism?

A

When a drug gets destroyed by the liver before entering the bloodstream

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4
Q

How can the intestinal gut flora metabolize drugs?

A

Bacteria can metabolize/biotransform drugs

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5
Q

Very hydrophilic drugs will usually get excreted ____

A

Unchanged

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6
Q

How are very hydrophilic drugs usually excreted?

A

By kidneys

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7
Q

Are lipophilic drugs usually metabolized?

A

Yes

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8
Q

What happens to lipophilic drugs when they enter the body?

A

They bind to proteins and distribute in fatty tissue and tend to persist in the body longer than hydrophilic drugs

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9
Q

Are lipophilic drugs excreted?

A

Not usually

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10
Q

What is the general goal of drug metabolism?

A
  • Chemically modify lipophilic drugs to increase their water solubility so that the metabolized drug can be excreted
  • Excretion!
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11
Q

What can metabolism do to drug activity and potency?

A
  • Can eliminate or decrease drug activity
  • Can alter drug activity
  • Can increase or decrease drug potency
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12
Q

What is it called when a drug is designed to undergo metabolism in order for it to be fully active?

A

Pro-drugs

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13
Q

What are the steps of phase 1 of drug metabolism?

A

Drug -> modified drug -> excretion

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14
Q

What are the steps of phase 2 of drug metabolism?

A

Modified drug -> modified drug-conjugate -> excretion

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15
Q

Do it always go phase 1 and then phase 2 for drug metabolism?

A

No, drugs can be eliminated by:

  • excreted unchanged
  • phase 1 only
  • phase 1 then phase 2
  • phase 2 only
  • phase 1, phase 2, and back to phase 1
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16
Q

What are examples of reactions that take place in phase 1 of drug metabolism?

A
  • Hydroxylation
  • Dealkylation
  • Oxide formation
  • Desulfuration
  • Dehalogenation
  • Alcohol oxidation
  • Deamination
  • Reduction
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17
Q

What is the most important phase 1 family of enzymes?

A

CYP enzymes

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18
Q

What do CYP enzymes require to function?

A

Electrons from NADPH and oxygen

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19
Q

Why do CYP enzymes need oxygen?

A

The oxygen is reduced while the drug is oxidized

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20
Q

How is the CYP enzyme family grouped?

A

By relatedness measured by amino acid similarity

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21
Q

How many CYP enzymes are in the body and where are they mainly found?

A
  • At least 30

- Mainly found in liver

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22
Q

What are the 2 groups of CYP enzymes and what are their functions?

A

1) CYP 1-4 are generally drug metabolizing

2) CYP 11, 17, 19, and 21 are generally the steroidogenic enzymes (but also participate in drug metabolism)

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23
Q

What are the most abundant CYPs in the liver?

A

CYP3A3, 3A4, and 3A5

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24
Q

What are the most important CYPs for drug metabolism?

A

CYP3A3, 3A4, and 3A5

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25
What takes place during generalized CYP reactions?
Oxidation reactions
26
The chain must be at least __ carbons for aliphatic hydroxylation to occur
2
27
What determines the rate of aliphatic hydroxylation?
Length of chain; longer chain = higher rate
28
What is aliphatic hydroxylation?
A hydroxyl group is added to the penultimate (2nd last) carbon of an aliphatic chain
29
What is important to note about aliphatic hydroxylation of aromatic compounds?
The carbon directly attached to the aromatic group is more likely to be hydroxylated
30
What determines the position of hydroxylation of an aromatic compound?
The R group and its position on the ring
31
What do ED R groups tend to do to aromatic hydroxylation?
Tend to increase hydroxylation and favour para-hydroxylation
32
What do EW R groups tend to do to aromatic hydroxylation?
Decrease hydroxylation
33
How can you eliminate aromatic hydroxylation?
Addition of EW substituents or halogens in the para position to the R group
34
What occurs in hydroxylation of fused aromatic ring systems?
Only 1 ring will be hydroxylated (typically the ring w/ no EW groups)
35
Are halogenated rings typically hydroxylated?
No
36
What occurs in N or S oxidation using a CYP enzyme?
N or S is double bonded to an O
37
What occurs in N, O, or S dealkylation using a CYP enzyme?
N, O, or S is broken from chain and gains a hydrogen
38
What occurs in deamination using a CYP enzyme?
NH3 is broken off chain
39
What is produced from epoxidation and how does this change if there is restricted rotation about the bond?
- Usually produces a diol | - Restricted rotation will produce a trans diol
40
Are epoxides reactive?
Very reactive
41
Epoxides are hydrolyzed by ____
Epoxide hydroxylase
42
Can epoxidation occur spontaneously?
Yes
43
What can happen to the trans diol that is formed from epoxidation?
Can be catalyzed by epoxide hydroxylase or can be non-enzymatic
44
What can epoxides do to proteins and why is this bad?
Can alkylate proteins, which is a potential source of toxicity produced by metabolism
45
What occurs in oxidative dehalogenation using a CYP enzyme?
CH2-X is transformed into CH=O (halogen is lost and carbon gains a double bonded oxygen)
46
What occurs in the CYP enzyme active site?
Heme has Fe and oxygen binds to Fe2+ and is converted into a reactive form
47
The substrate binding site of CYPs generally prefer _____
Hydrophobic substrates
48
What do many CYP inhibitors have and why?
Imidazole groups that bind to the oxygen and inhibit the CYP enzymes
49
What is the most prominent example of a CYP inhibitor and why?
- Azole antifungals; ketoconazole and itraconazole are most potent - They often have a large hydrophobic region that binds to CYP substrate binding pocket
50
Will a molecule with a very hydrophobic R group be a good CYP inhibitor?
Yes, more hydrophobic R group = more potent inhibitor
51
Are esterases and amidases CYP enzymes?
No, but perform hydrolysis reactions and are phase 1 enzymes
52
Where are esterases and amidases found?
Throughout the body and in blood
53
What are pro-drugs often designed as and why?
Esters or amides so that they are hydrolyzed by esterases or amidases
54
What is the main function of phase 2 enzymes?
Transfer an endogenous chemical to the drug
55
What are requirements of a phase 2 enzyme?
- Substrates can be unmodified or a modified drug from phase 1 - Activated endogenous chemical - Functional group on drug to modify
56
Why do phase 2 enzymes require an activated endogenous chemical?
Because it acts as a good leaving group for transfer of endogenous chemical to drug
57
Is the conjugated drug more or less hydrophilic than original drug?
Much more
58
What are the types of phase 2 conjugation and which is the most important?
- Glucuronide conjugation (most important) - Glutathoine conjugation - Methylation - Acetylation - Sulfate conjugation - Amino acid conjugation
59
What is the enzyme of glucuronide conjugation?
UDP-glucuronosyltransferases (UGT)
60
What is the activated endogenous chemical of glucuronide conjugation?
Uridine diphosphate glucuronic acid (UDP-GA)
61
What are the target functional groups of glucuronide conjugation?
- OH (most common) - SH - NH - COOH - R-NH-OH - R-S-OH
62
How is the product of glucuronide conjugation excreted if it is less than 250 Da?
Urine
63
How is the product of glucuronide conjugation excreted if it is more than 350 Da?
Feces
64
What is the enzyme of glutathoine conjugation?
Glutathoine S transferase (GST)
65
What is important to note about glutathoine S transferase (GST)?
- Tripeptide found in all tissues - Has a thiol group - Involved in scavenging reactive metabolites and free radicals - Often detoxifies toxic reactive metabolic intermediates
66
What is the activated endogenous chemical of glutathoine conjugation?
Gamma glutamyl-cystenyl-glycine (G-SH)
67
Can G-SH work without GST?
Yes, but slower
68
Is G-SH activated?
No
69
What are the target functional groups of glutathoine conjugation?
- Any electrophile | - Carbonyls, substituted aromatic rings, double bonds
70
How is the product of glutathoine conjugation excreted?
Mostly in feces
71
What is the enzyme of sulfate conjugation?
Sulfotransferase (ST)
72
What is the activated endogenous chemical of sulfate conjugation?
Phosphoadenosine phosphosulfate (PAPS)
73
What are the target functional groups of sulfate conjugation?
- OH - Phenols - Catachols - Hydroxylamines - Hydroxysteroids (estradiol)
74
How is the product of sulfate conjugation excreted?
Urine
75
What is the enzyme of amino acid conjugation? Which is most important?
Aminoacyl transferse (AA-T); most important is glycine
76
What is the activated drug of amino acid conjugation?
Drug-CoA
77
What is the target functional group of amino acid conjugation?
COOH
78
How is the product of amino acid conjugation excreted?
Urine
79
What is the enzyme of methylation?
Methytransferase (MTase)
80
What is the activated endogenous chemical of methylation?
S-adenosyl methionine (SAM)
81
What are the target functional groups of methylation?
O, N, and S
82
How is the product of methylation excreted?
Urine or feces
83
What is the enzyme of acetylation? Which is the most important?
Acetyl-transferase (AT); N-acetyl transferase is most important, also have O or S acetyl transferase
84
What is the activated endogenous chemical of acetylation?
Acetyl
85
What are the target functional groups of acetylation?
- N | - Sometimes O or S
86
How is the product of acetylation excreted?
Urine
87
Is acetylation likely to increase water solubility?
No
88
What does acetylation sometimes produce?
An inactive compound

Medicinal Chemistry (14 decks)

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