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PharmSci ADME > Metabolism > Flashcards

Metabolism Flashcards

1
Q

A drug that has high Cl is eliminated ____

A

faster

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2
Q

Metabolism is considered what types of pathways?

A

elimination
deactivation
detoxification

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3
Q

Drug metabolism can result in…

A
  • form metabolite more hydrophilic
  • deactivate active into inactive
  • detoxify toxic xenobiotics
  • activate inactive to active
  • activate inert into more reactive and toxic
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4
Q

Phase I metabolism includes what types of reactions?

A

oxidation
reduction
hydrolysis

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5
Q

Oxidation enzymes

A

CYPS, P450s, MAO, ADH, ALDH

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6
Q

Reduction enzymes

A

CYPs

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7
Q

CYP450s are responsible for metabolism of ___% of drugs

A

75%

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8
Q

Where are CYPs?

A

mostly microsomal in ER

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9
Q

How do CYPs work?

A

transfer O atom by aid of NADPH CYP450 reductase (POR)

transfers 2 electrons from NADPH

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10
Q

Which CYP is involved in metabolism of 50% of all drugs?

A

CYP3A4/5

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11
Q

Which CYP metabolism 90% of CYP substrates?

A 
1A2
2D6
2C9
2C19
2B6
3A4/5
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12
Q

Which CYP metabolism of 70% of all drugs?

A 
1A2
2D6
2C9
2C19
2B6
3A4/5
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13
Q

Induction and inhibition of CYPs is a major source of what?

A

DDI and drug food interactions

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14
Q

CYP2D6, 2B6, 2C9 and 2c19 expression is significantly influenced by what?

A

polymorphisms to give rise to poor and extensive metabolizers

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15
Q

CYP2D6 polymorphisms

A

need to screen before you take the drug

- need to know how you metabolize for dose

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16
Q

Metabolizing enzymes are located where?

A
  • membrane
  • microsomal via ER
  • mitochondria
  • nuclear
  • cytosolic
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17
Q

What are the 4 outcomes from metabolism of a drug?

A
  1. active –> inactive
  2. non-toxic –> toxic
  3. inactive prodrug –> active drug
  4. active –> active metabolite
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18
Q

What are the enzymatic processes of drug metabolism?

A

Phase I: structural modification

Phase II: conjugation

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19
Q

What enzymes are involved with hydrolysis?

A

esterases
amidases
epoxide hydrolases

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20
Q

CYPs must contain

A

heme containing proteins
P450 reductases
NADPH

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21
Q

What factors influence variability between CYP isoforms?

A
  • polymorphisms
  • gender
  • age
  • DDI
  • pathological conditions (liver disease)
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22
Q

Drugs primarily eliminated intact in urine are ____ suspected to inter and intra individual variation or DDI

A

less

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23
Q

Conjugation with polar moieties create what?

A

glucuroinic acid or sulfate groups

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24
Q

Conjugation with what decreases polarity?

A

alkyl or acetyl groups

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25
Q

Conjugation and kinetics

A

some have limited capacity (Vmax), cause non linear kinetics

- saturation

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26
Q

UGTs

A

transfer of glucuronic acid from UDPGA

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27
Q

UGT characteristics

A
  • low affinity
  • high capacity enzymes
  • polar and ionizable metabolites (increase MW)
  • facilitates renal and biliary excretion
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28
Q

SULTs

A

transfer of sulfate group from PAPs

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29
Q

SULTs characteristics

A
  • high affinity
  • low capacity enzymes
  • inactivation of steroids and bile acids
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30
Q

NATs

A

transfer of acetyl group from acetyl CoA

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31
Q

NATs characteristics

A
  • metabolite less polar than parent

- polymorphism

32
Q

GSTs

A
  • transfer GSH to reactive electrophilic species (ROS)

- eventually transformed into mercapturic acid derivatives

33
Q

What is the major source of bacterial metabolism?

A

gut microflora

34
Q

What are examples of spontaneous biotransformation?

A

hydrolysis of labile bonds

35
Q

What reactions are catalyzed by gastric acid?

A

hydrolysis of esters

36
Q

Significance of intestinal metabolism

A
  • orally administered drugs have higher concentrations in enterocytes
  • long resident times
  • in liver, there are alternative pathways if CYP3A4 is inhibited; in intestine no alternatives!
37
Q

T/F Liver metabolism is more extensive than intestinal metabolism of drugs

A

False; as extensive

38
Q

Vmax

A
  • max reaction speed at which all enzyme molecules are being used to catalyze the reaction
  • defines capacity of the reaction, related to enzyme expression levels (E) and its kcat
39
Q

Kcat

A

catalytic constant = turnover number

number of substrate molecules that one molecule of enzyme can convert to product per time

40
Q

Km

A
  • substrate concentration at which reaction rate (v) is half that of Vmax
  • defines affinity between substrate and enzyme
41
Q

Decreasing Km = _____ affinity

A

more

42
Q

Higher Vmax = _____ capacity

A

higher

43
Q

When [S} &laquo_space;Km…

A

Cl is concentration independent
1st order
linear

44
Q

At higher [S]…

A

Cl is concentration dependent
0 order
nonlinear
PK approaches saturation

45
Q

Homotropic cooperativity

A
  • biphasic kinetics
  • sigmoidal
  • substrate inhibition
46
Q

Heterotrophic acitvation/cooperativity

A

effector, a different chemical entity than substrate, increase reaction velocity of substrate without affecting enzyme expression

47
Q

Effector molecules

A

same or different chemical entity bind simultanesouly with substrate molecule to enzyme at distinct sites and affect rate of substrate binding

48
Q

IC50

A

concentration of inhibitor to reduce enzyme activity toward substrate by 50%

49
Q

What does IC50 depend on?

A

substrate concentration

50
Q

What is Ki independent of?

A

substrate concentration

51
Q

Ki or IC50: which can you compare inhibitors regardless incubation conditions?

A

Ki

52
Q

Competitive inhibition

A 
Vmax = no change
Km = increased
Vmax/km = decreased

**extent of inhibition decreased or completely reversed by increasing substrate concentration

53
Q

Noncompetitive inhibition

A 
Km = no change
Vmax = decreased
Vmax/km = decreased

** cannot be reversed by increasing substrate concentration

54
Q

Uncompetitive inhibition

A 
Km = decreased
Vmax = decreased
Vmax/km = no change
55
Q

Mixed inhibition

A 
Km = increase or decrease
Vmax = decreases

ratio of the 2 increases or decreases

56
Q

Mechanism based inhibition

A
  • AKA suicide inhibition
  • not instantaneous; time dependent
  • quasi irreversible non covalent coordination with heme group
  • catalytically formed reactive intermediates cause permanent/irreversible inactivation of enzyme
57
Q

Mechanism based inhibition effects

A
  • reaches max effect slowly

- lasts for a long period of time until a new functional enzyme synthesized

58
Q

Structural alerts may be considered as red flags for what type of inhibition?

A

mechanism based

59
Q

What does enzyme induction typically affect?

A

enzyme concentration rather than Kcat (activation/cooperativity)

60
Q

What are some examples of enzyme inducers?

A

barbiturates, carbamazepine, phenytoin
rifampicin
St John’s wort
phenobarbial

61
Q

Autoinduction

A

carbamazepine induces its own metabolism with time and/or higher doses

62
Q

Enzyme induction effects

A

slower onset and longer effect

63
Q

How does enzyme induction work?

A
  • activates nuclear receptor
  • translocates to nucleus
  • binds to response element in promotor region of target gene
  • induces its expression
64
Q

T/F only the protein-unbound fraction can be extracted by heptaocytes

A

True

65
Q

Intrinsic hepatic clearance

A
  • measure pure metabolic capability inherent to hepatic enzymes activity independent of other extra hepatic factors
  • sum of all enzymes involved
66
Q

Well stirred model

A

assumes liver is a single homogenous compartment

- concentration of unbound drug in effluent is in equilibrium with unbound drug in liver fluid

67
Q

What are the factors that affect hepatic clearance?

A
  • hepatic blood flow (Q)
  • protein binding (fu)
  • intrinsic clearance (Clint)
68
Q

High E

A

> 0.7

  • sensitive to changes in Q
  • flow or perfusion limited drugs
  • insensitive to changes in fu or Clint
69
Q

Low E

A

<0.3

  • sensitive to changes in fu and Clint
  • capacity limited drugs
  • insensitive to Q
70
Q

Within low E drugs, are highly protein bound drugs or low protein bound drugs more affected by changes in fu?

A

highly protein bound drugs (>90%)

71
Q

Well stirred model and AUC

A
  • Not affected by Q in low or high ER drugs in oral drugs!
72
Q

High E and AUC IV

A
  • AUC increase with decreasing Q

- no change in Clint

73
Q

Low E and AUC IV

A
  • AUC not affected

- AUC decrease with increasing Clint

74
Q

Which type of drugs are most vulnerable to metabolism based DDI?

A

highly permeable compounds (perfusion limited)

75
Q

Which type of drugs are most vulnerable to transporter based DDI?

A

Poorly permeable compounds but good substrates for uptake transporters

76
Q

Which type of drugs are not vulnerable to DDI?

A

poorly permeable compounds and are not substrates for uptake transporters (diffusion limited)

77
Q

In poorly permeable compounds but good substrates for uptake transporters, hepatic clearance is primarily determined by what?

A

rate of uptake rather than metabolism

PharmSci ADME (4 decks)

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