Lecture 4 (Drug Metabolism) Flashcards Preview

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Flashcards in Lecture 4 (Drug Metabolism) Deck (67):
1

Main site in body for drug metabolism?

liver

2

Liver is the site of ???

1st pass metabolism

3

Where else can drugs be metabolized in the body?

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

4

Very hydrophilic drugs will get excreted ____

unchanged
(they are already water soluble)

5

Lipophilic drugs are usually ______

metabolized

6

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

1 - they need to be metabolized

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

7

lipophilic drugs generally avoid excretion by _____

kidney

8

goal of drug metabolism?

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

9

Phase 1 metabolism?

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

oxidation (most common)
hydrolysis
reduction

10

Phase 2 metabolism?

biosynthetic conjugation

modified drug transforms to drug-conjugated

Glucuronidation
Acetylation (glutathione)
Sulfation

11

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

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

12

cytochrome P450 family of enzymes referred to as ___

CYP enzymes

13

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

heme

14

where do the electrons come from

NADPH

15

What is the general formula for Phase 1 CYP

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

*R = drug

16

CYP enzyme family is grouped by relatedness measured by ??

amino acid similarity

17

CYP 1 through 4 are known as ?

drug metabolizing enzymes

18

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

steroidogenic enzymes

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

19

first number refers to _____

family (having > 40% amino acid similarity)

20

letter refers to _____

subfamily (having > 59% amino acid similarity)

21

last number refers to ____

subtype of subfamily

22

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

-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

23

aliphatic hydroxylation:
longer the chain = ?

higher the rate

24

CYP reactions:
aromatic hydroxylation

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

25

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

one

26

typically rings with _____ and __ groups will not be hydroxylated

halogens

EW

27

CYP reactions:
alkene oxidation (epoxidation)

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

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

28

CYP reactions:
N or S oxidation

O is added to N or S

29

see slide 16 for:
N, O, or S dealkylation (v common)

ok man

30

CYP reactions:
deamination

see slide 16

31

What 3 ways can epoxides be hydrolyzed?

1) EH (epoxide hydrolase) or non-enzymatic

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

3) protein

*See slide 17

32

describe the CYP enzyme active site

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

Substrate binding site generally prefers _____ substrates

hydrophobic
(because we are trying to make it more hydrophilic)

34

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

imidazole

35

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

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

36

give 2 examples of azole antifungals

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

37

_____ is also an inhibitor but less potent

fluconazole

38

Are esterases/amidases CYPs?

NO

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

39

What are pro-drugs often designed as?

esters and amides

- so then they can be hydrolyzed by esterases or amides to produce an active drug

40

What do Phase 2 enzymes require?

-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

List the 6 types of Phase 2 conjugation

-glucuronide conjugation (most important)

-glutathione conjugation

-methylation

-acetylation

-sulfate conjugation

-amino acid conjugation

42

Glucuronide conjugation:
enzyme?

UGT

(UDP-glucuroosyltransferases)

43

Glucuronide conjugation:
activated endogenous chemical?

UDP-GA

(uridine diphosphate glucuronic acid)

44

Glucuronide conjugation:
target functional groups?

OH ( most common)
SH, NH, COOH, R-NH-OH, R-S-OH

45

Glucuronide conjugation:
if product

excreted in urine

46

Glucuronide conjugation:
if product > 350 Da ?

excreted in feces

47

Glutathione conjugation:
enzyme?

GST

(glutathione S transferase)

48

Glutathione conjugation:
activated endogenous chemical?

GSH

(yglutamyl-cystenyl-glycine)

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

49

Glutathione conjugation:
target functional groups?

any electrophile
carbonyls
substituted aromatic rings
double bonds

50

Glutathione conjugation:
mostly excreted in ?

feces

51

Describe GST (glutathione S transferase)

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

52

Sulfate conjugation:
enzyme?

ST

(sulfotransferase)

53

Sulfate conjugation:
activated endogenous chemical?

PAPS

(phosphoadenosine phosphosulfate)

54

Sulfate conjugation:
target functional groups?

OH
phenols
catechols
hydroxyl amines
hydroxysteroids (estradiol)

55

Sulfate conjugation:
excreted in ?

urine

56

Methylation:
enzyme?

MTase

(methytransferase)

57

Methylation:
activated endogenous chemical?

SAM :)

(S-adenosyl methionine)

58

Methylation:
target functional groups?

O, N, S

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

59

Methylation:
excretion ?

urine or feces

60

Acetylation:
enzyme?

AT

(acetyl transferase)

there can be NAT, OAT, or SAT

NAT = most common

61

Acetylation:
activated endogenous chemical?

acetyl CoA

(acetyl co enzyme A)

62

Acetylation:
target functional groups?

mainly N

sometimes O or S

63

Acetylation:
excreted in?

mostly urine

64

Amino acid conjugation:
enzyme?

AA-T

(aminoacyl transferase)

*most important in glycine

65

Amino acid conjugation:
activated endogenous chemical?

Drug-CoA

*drug is activated usually through COOH

66

Amino acid conjugation:
target functional groups?

COOH

67

Amino acid conjugation:
mostly excreted in ?

urine