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Med Chem > Lecture 4 (Drug Metabolism) > Flashcards

Lecture 4 (Drug Metabolism) Flashcards

1
Q

Main site in body for drug metabolism?

A

liver

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2
Q

Liver is the site of ???

A

1st pass metabolism

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3
Q

Where else can drugs be metabolized in the body?

A
  • secretion into bile
  • elimination in feces
  • kidneys (filter blood)
  • lungs (exhale drugs)
  • intestinal gut flora
  • skin and other organs
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4
Q

Very hydrophilic drugs will get excreted ____

A

unchanged

they are already water soluble

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5
Q

Lipophilic drugs are usually ______

A

metabolized

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6
Q

Why do lipophilic drugs tend to be in the body longer than hydrophilic drugs?

A

1 - they need to be metabolized

2- lipophilic drugs can bind to proteins that are distributed in fatty tissues

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7
Q

lipophilic drugs generally avoid excretion by _____

A

kidney

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8
Q

goal of drug metabolism?

A

chemically modify (metabolize) lipophilic drugs to increase their water solubility so they can be excreted by the kidney

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9
Q

Phase 1 metabolism?

A

drug becomes modified drug by:
-adding/exposing functional groups to make it more water soluble

oxidation (most common)
hydrolysis
reduction

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10
Q

Phase 2 metabolism?

A

biosynthetic conjugation

modified drug transforms to drug-conjugated

Glucuronidation
Acetylation (glutathione)
Sulfation

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11
Q

There are typically several routes of metabolism - why is this a good thing?

A

it is good that there is more than 1 route because if something affects one route - the drug will not accumulate in the body and pose a risk of potential toxicity

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12
Q

cytochrome P450 family of enzymes referred to as ___

A

CYP enzymes

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13
Q

CYP are ___ proteins that require electrons and molecular oxygen (O2) to function

A

heme

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14
Q

where do the electrons come from

A

NADPH

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15
Q

What is the general formula for Phase 1 CYP

A

R + NADPH + O2 + H+ —CYP–> R-OH + NADP+ + H2O

*R = drug

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16
Q

CYP enzyme family is grouped by relatedness measured by ??

A

amino acid similarity

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17
Q

CYP 1 through 4 are known as ?

A

drug metabolizing enzymes

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18
Q

CYP 11, 17, 19, 21 are the ??

A

steroidogenic enzymes

*these also participate in drug metabolism of drugs that are steroid like in structure

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19
Q

first number refers to _____

A

family (having > 40% amino acid similarity)

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20
Q

letter refers to _____

A

subfamily (having > 59% amino acid similarity)

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21
Q

last number refers to ____

A

subtype of subfamily

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22
Q

CYP reactions:
aliphatic hydroxylation
(omega-1 hydroxylation)
(subterminal hydroxylation)

A
  • on “next to last” (penultimate) carbon on aliphatic chain
  • chain has to have 2 or more carbons

*carbon directly attached to an aromatic group more likely to be hydroxylated

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23
Q

aliphatic hydroxylation:

longer the chain = ?

A

higher the rate

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24
Q

CYP reactions:

aromatic hydroxylation

A

ED R groups tend to increase hydroxylation and favours para hydroxylation (where the OH and R are directly across from each other)

EW R groups tend to decrease hydroxylation

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25
Q

In fused aromatic ring systems - usually only ___ ring will be hydroxylated

A

one

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26
Q

typically rings with _____ and __ groups will not be hydroxylated

A

halogens

EW

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27
Q 
CYP reactions:
alkene oxidation (epoxidation)
A

epoxide is very reactive and may decompose non-enzymatically in H2O

*alkene becomes an epoxide (three membered ring with O)

28
Q

CYP reactions:

N or S oxidation

A

O is added to N or S

29
Q

see slide 16 for:

N, O, or S dealkylation (v common)

A

ok man

30
Q

CYP reactions:

deamination

A

see slide 16

31
Q

What 3 ways can epoxides be hydrolyzed?

A

1) EH (epoxide hydrolase) or non-enzymatic

2) GST/ GSH
(glutathione s transferase/ glutathione)

3) protein
* See slide 17

32
Q

describe the CYP enzyme active site

A

heme group attached to an active oxygen (very electron deficient and reactive)

*oxygen is binded to the Fe2+ group and is converted into a reactive form

33
Q

Substrate binding site generally prefers _____ substrates

A

hydrophobic

because we are trying to make it more hydrophilic

34
Q

some drugs are CYP inhibitors and they have ____ groups on them that bind to the oxygen and inhibit the CYP enzymes

A

imidazole

35
Q

??? are the most prominent example of CYP enzyme inhibitors

A

azole antifungals
*they often also have large hydrophobic regions that bind to the CYP substrate binding pocket making them ideal CYP inhibitors

36
Q

give 2 examples of azole antifungals

A

ketoconazole
itraconazole
*they are the most potent azole anti fungal inhibitors of CYP enzymes

37
Q

_____ is also an inhibitor but less potent

A

fluconazole

38
Q

Are esterases/amidases CYPs?

A

NO

*but they do perform hydrolysis rxns and are Phase 1 enzymes

39
Q

What are pro-drugs often designed as?

A

esters and amides

  • so then they can be hydrolyzed by esterases or amides to produce an active drug
40
Q

What do Phase 2 enzymes require?

A
  • substrate that is an unmodified drug or a drug modified by Phase 1
  • require activated endogenous chemical (activated because it acts as a good leaving group for transfer of endogenous chemical to drug)
  • functional group on drug to modify
41
Q

List the 6 types of Phase 2 conjugation

A
  • glucuronide conjugation (most important)
  • glutathione conjugation
  • methylation
  • acetylation
  • sulfate conjugation
  • amino acid conjugation
42
Q

Glucuronide conjugation:

enzyme?

A

UGT

UDP-glucuroosyltransferases

43
Q

Glucuronide conjugation:

activated endogenous chemical?

A

UDP-GA

uridine diphosphate glucuronic acid

44
Q

Glucuronide conjugation:

target functional groups?

A

OH ( most common)

SH, NH, COOH, R-NH-OH, R-S-OH

45
Q

Glucuronide conjugation:

if product

A

excreted in urine

46
Q

Glucuronide conjugation:

if product > 350 Da ?

A

excreted in feces

47
Q

Glutathione conjugation:

enzyme?

A

GST

glutathione S transferase

48
Q

Glutathione conjugation:

activated endogenous chemical?

A

GSH

(yglutamyl-cystenyl-glycine)

*this is not activated - therefore is an exception to the rule

49
Q

Glutathione conjugation:

target functional groups?

A

any electrophile
carbonyls
substituted aromatic rings
double bonds

50
Q

Glutathione conjugation:

mostly excreted in ?

A

feces

51
Q

Describe GST (glutathione S transferase)

A
  • tripeptide found in all tissues
  • has a thiol group
  • toxic reactive metabolic intermediates of drugs are often detoxified by glutathione
52
Q

Sulfate conjugation:

enzyme?

A

ST

sulfotransferase

53
Q

Sulfate conjugation:

activated endogenous chemical?

A

PAPS

phosphoadenosine phosphosulfate

54
Q

Sulfate conjugation:

target functional groups?

A 
OH
phenols
catechols
hydroxyl amines
hydroxysteroids (estradiol)
55
Q

Sulfate conjugation:

excreted in ?

A

urine

56
Q

Methylation:

enzyme?

A

MTase

methytransferase

57
Q

Methylation:

activated endogenous chemical?

A

SAM :)

S-adenosyl methionine

58
Q

Methylation:

target functional groups?

A

O, N, S

*this may reduce water solubility but it is more important biochemically to inactivate endogenous compounds

59
Q

Methylation:

excretion ?

A

urine or feces

60
Q

Acetylation:

enzyme?

A

AT

(acetyl transferase)

there can be NAT, OAT, or SAT

NAT = most common

61
Q

Acetylation:

activated endogenous chemical?

A

acetyl CoA

acetyl co enzyme A

62
Q

Acetylation:

target functional groups?

A

mainly N

sometimes O or S

63
Q

Acetylation:

excreted in?

A

mostly urine

64
Q

Amino acid conjugation:

enzyme?

A

AA-T

(aminoacyl transferase)

*most important in glycine

65
Q

Amino acid conjugation:

activated endogenous chemical?

A

Drug-CoA

*drug is activated usually through COOH

66
Q

Amino acid conjugation:

target functional groups?

A

COOH

67
Q

Amino acid conjugation:

mostly excreted in ?

A

urine

Med Chem (11 decks)

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