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Analytical and Clinical > Week 4 - HPLC and Drug Metabolism > Flashcards

Week 4 - HPLC and Drug Metabolism Flashcards

1
Q

What is biotransformation?

A

conversion of free drug into metabolites or excreted product

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2
Q

What does ADME stand for?

A

Absorption
Distribution
Metabolism – anabolism, catabolism
Excretion

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3
Q

What part of ADME is drug elimination

A

Metabolism – anabolism, catabolism
Excretion

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4
Q

WHY IS THE STUDY OF DRUG METABOLISM &
ELIMINATION IMPORTANT?

A
  • The route of metabolism of a drug can determine its ultimate
    pharmacological or toxicological activity
  • May impact on dose and frequency
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5
Q

Where does a lot of the biotransformation processes happen?

A

liver

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6
Q

What is anabolism?

A

adding components

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7
Q

What is catabolism?

A

breaking down

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8
Q

Characteristics of intravenous drug administration?

A
  • active straight away
  • likely to ass liver/kidney
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9
Q

What is the first pass effect?

A

first thing that happens to drug which is metabolism of drug occurring before entering the systemic circulation

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10
Q

What is the drug metabolised by in the first pass effect?

A
  • Enzymes in GIT (also not all will be absorbed)
  • Liver
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11
Q

What are the consequences of the first pass effect?

A

means that there is not 100% bioavailability of the drug and less than 100% of drug enters the circulatory system
- therefore we need more of the drug

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12
Q

What type of variation in humans affect drug absorption?

A

metabolic rate and enzyme rate

drugs can also be slowed down when intestinal blood flows changes - during eating etc

having two different drugs at the same time can also cause incomplete drug absorption

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13
Q

How does body remove polar/hydrophilic drugs from blood?

A

urine and faeces

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14
Q

What needs to be done to non-polar and lipophilic drugs?

A

transform in liver

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15
Q

What are the characteristics of most drugs?

A

they are non-polar and lipophilic

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16
Q

Where is the primary location where drug metabolism occurs?

A

Primarily in the liver but can occur in all organs

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17
Q

What is metabolism?

A

process of converting chemicals to more
polar metabolites

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18
Q

What happens to the polarity of drugs/metabolites after phase 1 and 2?

A

polarity increases

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19
Q

What are the two phases of drug metabolism?

A

phase 1 and 2

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20
Q

What is the purpose of phase one?

A

activation of the drug - to make it more active

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21
Q

How does the drug become more active in phase 1?

A

undergoes

oxidation
hydroxylation
dealkylation
deamination
hydrolysis

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22
Q

What is formed after phase 1?

A

a derivative

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23
Q

What is a derivative?

A

a compound that is derived from a similar compound by a chemical reaction.

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24
Q

What is the purpose of phase 2?

A

to form a conjugate from a derivative through conjugation

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25
Q

What is a conjugate?

A

A compound formed by chemically joining two or more different substances

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26
Q

What is conjugation?

A

The process of covalently linking drugs to various natural or synthetic molecule carriers for specific applications

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27
Q

What does oxidation do to drug molecules?

A

increases water solubility

introduces functional group to make it easier to metabolise

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28
Q

What is an electrophile?

A

electron acceptor

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29
Q

What is a nucleophile?

A

provide electron pair to get new covalent bond

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30
Q

What process in phase one produces electrophiles?

A

oxidation of lipophilic molecules

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31
Q

What process in phase one produces nucleophiles?

A

hydrolysis and reduction

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32
Q

What is the purpose of phase 1 and 2?

A

convert lipophilic molecules into hydrophilic

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33
Q

What do electrophiles produced from phase 1 undergo?

A

glutathione conjugation to produce hydrophilic molecule

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34
Q

What do nucleophiles produced from phase 2 undergo?

A

sulfation

acetylation

glucuronidation

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35
Q

What type of reactions occur in phase 1?

A

reactions are catabolic

  • Oxidation –most important, catalysed by cytochrome P450 enzymes
  • Reduction
  • Hydrolysis
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36
Q

Where is P450 from?

A

liver

  • lots of genetic variation in cytochrome - which influences drug metabolism
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37
Q

What is a feature of the products produced from phase one?

A

metabolites can be more toxic or carcinogenic than parent drug
- this is when they need extra metabolic processes

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38
Q

What occurs in phase one?

A

introduction of reactive group
- known as a process of functionalisation
- group acts as a point of attack for conjugating system

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39
Q

What type of reactions occur in phase two?

A

synthetic/anabolic

40
Q

What does phase two reactions involve?

A

conjugation - attachment of substituent group

  • Glucuronic acid
  • Sulphate
  • Amino acids
  • Glutathione
  • Acetylation
41
Q

What is the aim of phase 2?

A

to activate end product

42
Q

What are the exceptions of phase 2?

A

exceptions -active sulphate metabolite of minoxidil (K+channel activator)

43
Q

Where does phase 2 mainly take place?

A

in the liver

  • If drug molecule or Phase 1 product has a suitable ‘handle’, it is susceptible
    to conjugation
  • Handle -hydroxyl, thiol or amino group
44
Q

What type of drugs are more easily transported?

A

lipophilic are more easily transported than hydrophilic

45
Q

Why are polar molecules a problem?

A

they need to be transported actively rather than passively

46
Q

What organ is important in phase 1?

A

liver

47
Q

Where are drug metabolising enzymes located?

A

embedded in the smooth ER

48
Q

What type of enzymes are embedded?

A

microsomal enzymes

49
Q

What happens to the drug to interact with these enzymes?

A

crosses the plasma membrane

50
Q

What happens to polar drugs?

A

Polar molecules move less readily unless transport system – polar drugs partly
excreted unchanged in urine

51
Q

What does CYP450 use as cofactor?

A

heme as a cofactor in their catalytic activity

52
Q

What phase is CYP more involved in?

A

phase 1 of metabolism

53
Q

Characteristics of CYP450

A

Superfamily

Differ in sensitivity to inhibition/induction and specificity of reaction they
catalyse

Distinct but overlapping substrate specificities

54
Q

MIXED-FUNCTION OXIDASE REACTION
(CYTOCHROME P450; CYP) EQUATION

A

NADPH + O2 + RH NADP+ + H2O + ROH

55
Q

Where is P450 found in?

A

endoplasmic rectilium

liver, kidney, lungs, intestine

56
Q

What does a mixed-function oxidase reaction require?

A

substrate, enzyme, molecular oxygen

57
Q

What is a mixed-function oxidase reaction catalysed by?

A
  1. Cytochrome P450
  2. NADPH-cytochrome P450 reductase
58
Q

What is an example of species differences of P450?

A

rats and humans developed colon cancer but not monkeys when eating bbq food
- dietary amines and genotoxic products

59
Q

What are characteristics of P450 expression?

A

polymorphism

environment – enzyme inducers and inhibitors e.g. grapefruit
juice inhibits enzymes, brussels sprouts induce P45. Clinically
important

60
Q

CYP2D6 : GENOTYPE/PHENOTYPE VARIABILITY

A

poor metabolizer
– little or no CYP2D6 function

intermediate metabolizers
– metabolize drugs at a rate somewhere
between the poor and extensive metabolizers

extensive metabolizer
– normal CYP2D6 function

ultrarapid metabolizer
– multiple copies of the CYP2D6 gene are expressed, so greater-than-normal CYP2D6 function occurs

61
Q

Is P450 the only enzyme involved in drug metabolism?

A

no there are others

  • Suxamethonium hydrolysed by plasma cholinesterase
  • Ethanol metabolised by alcohol dehydrogenase + CYP2E1
  • Xanthine oxidase inactivates 6-mercaptopurine
  • MAO – inactivates biologically active amines – e.g. NA, tyramine, 5-HT

Hydrolysis –
Ester and amide (less readily) bonds susceptible to hydrolytic cleavage
Warfarin – reduction of ketone to OH by CYP2A6

62
Q

PHASE II REACTIONS

A

Insertion of a chemical group

Glucuronyl

Sulphate

Methyl

Acetyl

63
Q

What happens if there is an enzyme that is missing?

A

its find because other enzymes have different functional groups that can make up for it

64
Q

What drugs create the R -OH glucuronide conjugation?

A

paracetamol, aspirin, morphine

65
Q

What drugs create the R- COOH glucuronide conjugation?

A

clofibrate, nicotinic acid

66
Q

What drugs create the R- NH2 glucuronide conjugation?

A

dapsone, sulphafurazole, meprobamate

67
Q

What drugs create the R- SH glucuronide conjugation?

A

2-mercapto-benzothiazole

68
Q

What are the endogenous substrates of glucoronide conjugation?

A

bilirubin, steroid hormones, thyroxine and catechols

69
Q

Characteristic of glucose

A

energy rich donor
- replacement of CH for H molecule of carbon 6

70
Q

What are the two molecules glucose is turned into?

A

glycolysis; glycogenesis

glucuronic acid

71
Q

What is the enzyme required when converting glucose into other molecules?

A

UDP glucuronosyl transferases

72
Q

GLUTATHIONE (GSH) CONJUGATION:
GLUTATHIONE S-TRANSFERASES - DOES IT REQUIRE ACTIVATION?

A

no
- they are electrophilic substrates

73
Q

Why is steroselectivity important?

A

Clinically important drugs e.g. warfarin, cyclophosphamide – mixtures of
stereoisomers

Different pharmacological effects

Differences in metabolism & pathways

Toxicity – linked to one stereoisomer – impact on new drugs

74
Q

Glutathione (GSH) conjugation - What happens to the conjugates?

A

conjugates can either be excreted or processed further

75
Q

What base is P450?

A

haem based

76
Q

What can enzyme induction increase?

A

drug toxicity or carcinogenicity

77
Q

What do phase one drugs tend to be?

A

reactive - toxic - carcinogenic

78
Q

How can we exploit the fact that phase 1 drugs tend to be reactive?

A

sometimes we need very reactive phase on metabolites

79
Q

Can some drugs act as inhibitors?

A

yes

80
Q

What type of inhibition can P450 do?

A

competitive inhibition

non-competitive inhibition

mechanism-based

81
Q

P450 - Competitive Inhibition Example

A

eg. quinidine - not substrate

82
Q

P450 Non-Competitive Inhibition

A
  • reversible
  • eg. ketoconazole
  • complex with Fe 3+ from haem iron of CYP3A4
83
Q

P450 Mechanism-Based

A
  • requires oxidation by P450 enzyme
    eg. oral contraceptive gestodene
  • oxidation product (epoxide intermediate of gestodene) binds covalently enzyme which destroy itself - suicide inhibiton
84
Q

Microsomal enzyme induction

A

Rifampicin, ethanol, carbamazepine - incr. activity of enzymes with repeated
admin

Carcinogenic chemicals have this effect e.g. benzypyrene

Can increase drug tox/carcinogenic can be exploited therapeutically

85
Q

ACTIVE DRUG METABOLITES

A

Pro-drugs

?deliberate design – drug delivery
e.g. aspirin inhibs platelet function and has anti-inflammatory activity but
hydrolysed to salicylic acid (anti-inflammatory not anti-platelet)

Metabolites may have similar effects to parent compound e.g.
benzodiazepines

toxicity eg. methanol and ethylene glycol

86
Q

How can other drugs interact with other drugs?

A

Slow onset of induction
Slow recovery,
Selective induction

it may affect how fast drug is metabolised and increase tolerance

87
Q

What can enzyme inhibition in the context of drugs?

A

Slow metabolism, increases action of drugs normally inactivated by enzyme

88
Q

What is a consequence of inhibiton?

A

therapeutic effects
- eg. disulfiram (aldehyde dehydrogenase inhib)
-> produces adverse reaction to ethanol, also inhibits metabolism of other drugs

89
Q

What does inhibition to the conversion of a prodrug to active metabolite result in?

A

loss of activity
eg. proton inhibitors (such as omeprazole) and anti platelet drug clopidogrel which is widely co-prescribed

90
Q

What do liver cells do?

A

transports substances from plasma to bile using transport system

eg. organic cation transporters (OCTs), organic anion transporters (OATs) and P-gylcoproteins (P-gps)

91
Q

Enterohepatic circulation steps

A

hydrophilic drug conjugates (esp glucuronides) concentrated in bile and delivered to the intestine

glucuronide can be hydrolysed, regenerating active drug;

free drug

reabsorbed

cycle repeated - reservoir of recirculating drug

eg morphine

92
Q

Renal clearance

A

volume of plasma containing the amount of substance that is removed from the body by kidneys in unit time

93
Q

What are the three processes that account for renal drug excretion?

A
  1. glomerular filtration
  2. active tubular secretion
  3. passive reabsorption
    - diffusion from the concentrated tubular fluid back across tubular epithelium
94
Q

What are the mechanisms by which one drug can affect the rate of renal excretion of another are:

A

altering protein binding (hence filtration)

inhibiting tubular secretion

altering urine flow and/or urine pH

95
Q

INDIVIDUAL VARIATION

A

Ethnicity – ethanol, propranolol

Age - hepatic microsomal enzyme activity declines

Pregnancy - Cardiac output increases - increased renal blood flow and
GFR, increased renal elimination of drugs

Disease

Drug interaction

Pharmokinetics interaction

96
Q

GENETIC VARIATION

A

Plasma cholinesterase deficiency – suxamethonium

Drug acetylation deficiency

Drug targeting

97
Q

What does the entroepatic circulation transport?

A

different conjugates

Analytical and Clinical (11 decks)

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