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Flashcards in Drug metabolism Deck (116)
1

Processes that prevent continuous drug action

elimination/excreation
metabolism

2

Drug metabolites are usually more ________ then the drug ingested thus easliy excreated

poloar

3

most drugs enter the body _______ thus are difficult to excrete

lipophilic

4

In most cases metabolism will take active drug-->

inactive metabolite

5

A drug that is converted to active form by drug metabolizing enZ

prodrug

6

a prodrug is inactive until

metabolized

7

the more drugs we take the more at risk we are for

adverse affects

8

Drugs withdrawn from the market often d/t this reason

drug-drug interactions d/t drug metabolism

9

These guys do oxidation, reduction, dealkylation or hydrolysis

Phase I enZ

10

This enZ will often introdue or reaveal a functional group

Phase I enZ

11

Phase I enZ actions

oxidation, reduction, dealkylation or hyrolysis and introduce or reveal a functional group

12

These guys have conjugation of durg or durg metaboliet to endogenous substrate molecule

Phase II enZ

13

responsible for : Drug + conjugant--> Drug-conjugant

Phase II enZ

14

CYPs are examples of

Phase I enx

15

CYPs will often

make lipophilic drugs more soluble in water

16

These guys add large, polar conjugates to make drug super water soluble

phase II

17

Common location for drug metabolizing agents

portals of entry/exit
liver (HIGHEST)
GI, kidneys, lungs

18

Subcellularly where are the Phase I enZ located ?

In the SER microsomes

19

Subcellularly, where are phase II enZ located?

most are cytosilc

20

What venous system will take drugs to liver from the GI system

portal venous sytem

21

What drug administration is exposed to 1st pass effect

orally administered

22

Significant drug metabolism can occur before reaching general circulation d/t

first pass in intestines and liver

23

Drugs exposed to 1st pass will need _____ dose

higher

24

bioavialibty will ______ d/t first pass

lower F

25

F for IV administration

1 or 100%

26

What are two reasons for poor F

poor absorption or large first pass effect

27

Morphines's F d/t first pass

.33

28

If i gave IV dose of 10 mg of morphine to relieve pain, what oral dose would i need to match that?

30 mg

29

Two key Phase I enZ

Cytochrome P450s = CYPs
Flavin-containing monooxygenases

30

Cytochrome P450s and Flavin-containing monooxygenases are examples of:

Phase I enZ

31

P450's are anchored to:

outer face of ER

32

Core of P450's

Fe

33

P450's conjugate what to our substrates (drug)

O2 and we get S-OH +H20

34

P450 reductase use what to get the 2e- to add to our substrate?

NADPH --> NADP + 2e-

35

molecular ration of P450s per P450 reductase

10-20 P450s: 1 P450reductase

36

CYP stands for

cytochrome

37

CYP2B10: 2 stands for

gene family

38

CYP2B10: B stands for

Gene subfamliy

39

CYP2B10: 10 stands for

isoform

40

Human P450's has _____ families

18

41

3 P450's involved in drug metabolism

CYP1, CYP2, CYP3

42

There are _____ human P450 genes
with _____ of them involved in drug metabolism

57
15

43

Inidivudual differences in _____ result in big difference of catyltic activity and drub metabolism

isofrm

44

This CYP handles 50% of drug metabolism

CYP3A

45

CYP3A handles____ % drug metabolism

50

46

This cyp handles 25% drug metabolism

CYP2D6: DEPRESSENTS

47

This CYP handles 19% drug metabolizm

CYP2C19: includes warfarin, phenytoin

48

Relative CYP isoform content does/does not equate to significance in role of drug metabolism

does not

49

CYP 2D6 responsible for metabolism of _____%
and has ______% expression

25% drugs
1.5% is expressed

50

FMO stands for

flavin-containig monooxygenase

51

What are the substrates for flavin monooxygenase (FMO)

soft nucleophiles like N, SP or Se

52

Does FMO react with endogenous soft nuecleophiles?

nope, just interacts with exogenous soft Nu's

53

what are expamples of endogenous soft nucelophiles

glutathione or cysteine

54

FMO's have broader or more specific substarte profile then P450's

broader

55

What type of products do Flavin-containing monooxygenases procude?

more polar and less toxic then CYPs

56

What results in broad substrate range for FMO's?

it's hydorperoxyflavin intermediates

57

What FMO is expressed in liver, brain and kidney?

FMO3

58

FMO3 makes up 2-3% of protein in

kidney

59

key FMO in liver

FMO3

60

Glucuronidation, sulfination and Acetylation are exapmles of

phase II enZ

61

UDP-glucoronic acid is example of

phase II enZ that does glucuronidation

62

PAPS is used in

sulfination; a phase II enZ

63

Acetyl Co-A involved in what?

acetylation in phase II enZ

64

Gluthathione conjucation is type of

phase II enZ

65

EnZ responsible for glucuronidation?

UDP-glucuronosyl transferase (UGT)

66

EnZ responsible for acetylation

N-acetyltransferase (NAT)

67

EnZ responsible for sulfination

Slufotransferases (SULT)

68

EnZ responsible for Glutathione conjucation

Glutathione S- transfereases (GST)

69

(NAT) stands for

N-acetyltransferase

70

(SULT) stands for

Sulfotransferases

71

(GST) stands for

Glutathione S- transfereases

72

(UGT) stands for

UDP-glucuronosyl transferase

73

IG, Phase II enZ makes metabolites more:

polar and less toxic

74

NAT does what to metabolites

makes some more polar, others less polar but makes most less toxic

75

Phase II enZ resposible for metabolism of almost half drugs

UGTs

76

bilirubin is metabolized by which phse II enz

UGT's

77

What affects the Vmax of the Phase II enZ?

amount of conjugant available

78

Glucuronidation has _____ conjugant capacity and ______ amt of raw materials for conjugation

High conjugation capacity
High amt of materials available

79

Sulfonation has ______ conjugation capacity and ______ abundance of raw materials for conjucation available

Low conjucation capacity
low abundance of raw materials

80

Gutathione conjucation has ______ conjucation capacity and _____ abundance of raw materials for conjucation

low conjucgation capacity
low materials (humans have high GSH initially, but gets rapidly depleated)

81

Two most common types of drug metabolism interactions:

EnZ induction
EnZ inhibition

82

Exposure to certain drugs/enviro chemicals will upregulate durg metabolizing enZ amount and or activity via transcription increase:

EnZ Induction

83

end result of enZ induction

more enZ d/t increased transcription = faster metabolism

84

Ethanol is an inducer of:

CYP2E1

85

Are Phase II enZ suseptible to enZ induction?

yes, UGTs and GST's are induced by stuff like tobaccoo smoke, PAH or benzoapyrene

86

A single inducer can affect _____ drugs handled by that enZ

many drugs

87

EnZ indcuction increases

drug metabolism

88

Induction has what sort of affect on drug effects

can increase or decrease them
--depends on if metabolite is inactive or active

89

How long does induction take?

1-2 days

90

Are inducers quantally equal?

no

91

Inducers of specific isoforms (CYP isoforms) are substrates (T/F)

F: they may or may not be substrates

92

T/F: all substartes are inducers

fales, NOT all substrates are inducers

93

Some inducers are substartes (T/F)

true

94

Inhibitors of drug metabolizing enZ will inhibit enZ activity, but not:

gene expression

95

Drug inhibitors include:

competitive and non-competitive

96

3 types of P450 Inhibitors

Competitive substrates
Bind CYP heme--distrupts catalytic activity (non-competitive)
Suicide inhibitors (irreversible and non-competitive)

97

Major cauase of CYP releated drug interactions are due to:

competitive substrates

98

By binding CYP heme, these P450 inhibitors will:

distrupt catalytic activity (non-competitive)

99

How long does enZ inhibition take

immediate effect

100

How much does inhibition affect drug metabolism

highly variabel: depends on enZ and inhibitor and could be small or large effect

101

Serveral CYP2D6 inhibitors will reduce it's activity to:

nearly zero

102

Grapefruit juice will _______ drug absorption

INCREASE

103

Grapefruit juice inhibits this intestinal CYP

CYP3A

104

By inhibiting CYP3A, grapeftruit juice will

increase net amount abosorbed to general circulation

105

the responsible ingrediant in grapefruit that inhibits intestinal CYP3A

furanocourmarin

106

Grapefruit juice is a big no for this CYP that handles 50% of drug metabolizm

CYP3A

107

FMO's are _______induced or inhibited by clinically used drugs

NOT significantly

108

These guys are less suseptible to competitive subtrate inhibition than P450's

FMOs

109

Whats the benefit to drugs that are handled by FMO's

less potential for metabolic drug-drug interactions

110

other factors that affect drug metabolism

age, genetics, disease states, gender

111

most common cause of acute hepatic failure in US

acetaminophen use

112

Second most common cause of liver fail requiring transplant

acetaminophen use

113

First line Phase II's that breakdown Acetaminiophen

SULT and UGT

114

What CYP will act on acetaminophen

CYP2E1

115

What will induce action of CYP2E1

ethenol

116

Product of acetaminophen--> CYP2E1 is

toxic and needs to be broken down by GST