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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
Q

What takes place during generalized CYP reactions?

A

Oxidation reactions

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26
Q

The chain must be at least __ carbons for aliphatic hydroxylation to occur

A

2

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27
Q

What determines the rate of aliphatic hydroxylation?

A

Length of chain; longer chain = higher rate

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28
Q

What is aliphatic hydroxylation?

A

A hydroxyl group is added to the penultimate (2nd last) carbon of an aliphatic chain

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29
Q

What is important to note about aliphatic hydroxylation of aromatic compounds?

A

The carbon directly attached to the aromatic group is more likely to be hydroxylated

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30
Q

What determines the position of hydroxylation of an aromatic compound?

A

The R group and its position on the ring

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31
Q

What do ED R groups tend to do to aromatic hydroxylation?

A

Tend to increase hydroxylation and favour para-hydroxylation

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32
Q

What do EW R groups tend to do to aromatic hydroxylation?

A

Decrease hydroxylation

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33
Q

How can you eliminate aromatic hydroxylation?

A

Addition of EW substituents or halogens in the para position to the R group

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34
Q

What occurs in hydroxylation of fused aromatic ring systems?

A

Only 1 ring will be hydroxylated (typically the ring w/ no EW groups)

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35
Q

Are halogenated rings typically hydroxylated?

A

No

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36
Q

What occurs in N or S oxidation using a CYP enzyme?

A

N or S is double bonded to an O

37
Q

What occurs in N, O, or S dealkylation using a CYP enzyme?

A

N, O, or S is broken from chain and gains a hydrogen

38
Q

What occurs in deamination using a CYP enzyme?

A

NH3 is broken off chain

39
Q

What is produced from epoxidation and how does this change if there is restricted rotation about the bond?

A
  • Usually produces a diol

- Restricted rotation will produce a trans diol

40
Q

Are epoxides reactive?

A

Very reactive

41
Q

Epoxides are hydrolyzed by ____

A

Epoxide hydroxylase

42
Q

Can epoxidation occur spontaneously?

A

Yes

43
Q

What can happen to the trans diol that is formed from epoxidation?

A

Can be catalyzed by epoxide hydroxylase or can be non-enzymatic

44
Q

What can epoxides do to proteins and why is this bad?

A

Can alkylate proteins, which is a potential source of toxicity produced by metabolism

45
Q

What occurs in oxidative dehalogenation using a CYP enzyme?

A

CH2-X is transformed into CH=O (halogen is lost and carbon gains a double bonded oxygen)

46
Q

What occurs in the CYP enzyme active site?

A

Heme has Fe and oxygen binds to Fe2+ and is converted into a reactive form

47
Q

The substrate binding site of CYPs generally prefer _____

A

Hydrophobic substrates

48
Q

What do many CYP inhibitors have and why?

A

Imidazole groups that bind to the oxygen and inhibit the CYP enzymes

49
Q

What is the most prominent example of a CYP inhibitor and why?

A
  • Azole antifungals; ketoconazole and itraconazole are most potent
  • They often have a large hydrophobic region that binds to CYP substrate binding pocket
50
Q

Will a molecule with a very hydrophobic R group be a good CYP inhibitor?

A

Yes, more hydrophobic R group = more potent inhibitor

51
Q

Are esterases and amidases CYP enzymes?

A

No, but perform hydrolysis reactions and are phase 1 enzymes

52
Q

Where are esterases and amidases found?

A

Throughout the body and in blood

53
Q

What are pro-drugs often designed as and why?

A

Esters or amides so that they are hydrolyzed by esterases or amidases

54
Q

What is the main function of phase 2 enzymes?

A

Transfer an endogenous chemical to the drug

55
Q

What are requirements of a phase 2 enzyme?

A
  • Substrates can be unmodified or a modified drug from phase 1
  • Activated endogenous chemical
  • Functional group on drug to modify
56
Q

Why do phase 2 enzymes require an activated endogenous chemical?

A

Because it acts as a good leaving group for transfer of endogenous chemical to drug

57
Q

Is the conjugated drug more or less hydrophilic than original drug?

A

Much more

58
Q

What are the types of phase 2 conjugation and which is the most important?

A
  • Glucuronide conjugation (most important)
  • Glutathoine conjugation
  • Methylation
  • Acetylation
  • Sulfate conjugation
  • Amino acid conjugation
59
Q

What is the enzyme of glucuronide conjugation?

A

UDP-glucuronosyltransferases (UGT)

60
Q

What is the activated endogenous chemical of glucuronide conjugation?

A

Uridine diphosphate glucuronic acid (UDP-GA)

61
Q

What are the target functional groups of glucuronide conjugation?

A
  • OH (most common)
  • SH
  • NH
  • COOH
  • R-NH-OH
  • R-S-OH
62
Q

How is the product of glucuronide conjugation excreted if it is less than 250 Da?

A

Urine

63
Q

How is the product of glucuronide conjugation excreted if it is more than 350 Da?

A

Feces

64
Q

What is the enzyme of glutathoine conjugation?

A

Glutathoine S transferase (GST)

65
Q

What is important to note about glutathoine S transferase (GST)?

A
  • Tripeptide found in all tissues
  • Has a thiol group
  • Involved in scavenging reactive metabolites and free radicals
  • Often detoxifies toxic reactive metabolic intermediates
66
Q

What is the activated endogenous chemical of glutathoine conjugation?

A

Gamma glutamyl-cystenyl-glycine (G-SH)

67
Q

Can G-SH work without GST?

A

Yes, but slower

68
Q

Is G-SH activated?

A

No

69
Q

What are the target functional groups of glutathoine conjugation?

A
  • Any electrophile

- Carbonyls, substituted aromatic rings, double bonds

70
Q

How is the product of glutathoine conjugation excreted?

A

Mostly in feces

71
Q

What is the enzyme of sulfate conjugation?

A

Sulfotransferase (ST)

72
Q

What is the activated endogenous chemical of sulfate conjugation?

A

Phosphoadenosine phosphosulfate (PAPS)

73
Q

What are the target functional groups of sulfate conjugation?

A
  • OH
  • Phenols
  • Catachols
  • Hydroxylamines
  • Hydroxysteroids (estradiol)
74
Q

How is the product of sulfate conjugation excreted?

A

Urine

75
Q

What is the enzyme of amino acid conjugation? Which is most important?

A

Aminoacyl transferse (AA-T); most important is glycine

76
Q

What is the activated drug of amino acid conjugation?

A

Drug-CoA

77
Q

What is the target functional group of amino acid conjugation?

A

COOH

78
Q

How is the product of amino acid conjugation excreted?

A

Urine

79
Q

What is the enzyme of methylation?

A

Methytransferase (MTase)

80
Q

What is the activated endogenous chemical of methylation?

A

S-adenosyl methionine (SAM)

81
Q

What are the target functional groups of methylation?

A

O, N, and S

82
Q

How is the product of methylation excreted?

A

Urine or feces

83
Q

What is the enzyme of acetylation? Which is the most important?

A

Acetyl-transferase (AT); N-acetyl transferase is most important, also have O or S acetyl transferase

84
Q

What is the activated endogenous chemical of acetylation?

A

Acetyl

85
Q

What are the target functional groups of acetylation?

A
  • N

- Sometimes O or S

86
Q

How is the product of acetylation excreted?

A

Urine

87
Q

Is acetylation likely to increase water solubility?

A

No

88
Q

What does acetylation sometimes produce?

A

An inactive compound

Medicinal Chemistry (14 decks)

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