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GI > Drug Metabolism > Flashcards

Drug Metabolism Flashcards

1
Q

definition of adsorption

A

interaction of drug with solid surface

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2
Q

definition of absorption

A

crossing biological barriers for therapy

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3
Q

definition of distribution

A

drug spreading evenly in the body - even to non-target sites

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4
Q

definition of metabolism

A

processing of drugs

dome are excreted unchanged

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5
Q

definition of excretion

A

high molecular weight drugs and their conjugates move along the bile duct and are excreted in faeces

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6
Q

what s t1/2

A

time taken for half the drug to be excreted

affects dosing interval

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7
Q

what is polypharmacy

A

pt taking more than six drugs

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8
Q

heavy molecules excretion route

A

move down bile duct and are passed with faeces (biliary/faecal route)

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9
Q

function of b-D-glucuronidase

A

enzyme at the end of the gut
strips off b-D-glucuronides (water-soluble sugar acids)
essential for use in the body
non-specific enzyme so drugs are also metabolised, acid/sugar groups are removed from drugs unless they are lipophilic

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10
Q

processing of lipophilic drugs

A

drug is reabsorbed instead of processed by b-D-glucuronidase, then transferred back to the liver and reabsorbed/reconjugated to be processed again
gives the drug a long halflife but is uncommon

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11
Q

what is a xenobiotic

A

metabolism of foreign bodies

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12
Q

phase 1

A

introducing or revealing a functional group

add or cleave groups

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13
Q

phase 2

A

conjugation

addition of bond to make drug more water-soluble or gives higher molecular weight >400Da

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14
Q

weight for biliary/faecal excretion

A

> 400Da

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15
Q

what happens to enzymes in drug metabolism

A

induced
amplified at gene level (can result in less effective drugs with similar groups or have more metabolising enzymes so the drug becomes less effective)

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16
Q

important phase 1 enzymes

A

CYP
non-specific esterases
amidases (cleave peptide bonds)

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17
Q

three types of peptidases

A

exodases (cleave from outside)
endodases (cleave from inside)
exopeptidases (N for amide cleaving and C for acid cleaving)

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18
Q

esters

A

non-polar and can diffuse across a membrane (lipid bilayer) so drugs can diffuse into the target cell
esters have no biological activity so esterases are able to modify in a prodrug reaction

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19
Q

phase 2 enzymes

A

bond-forming enzymes:
9% glutathione-S-transferase (GST)
90% UDP- glucuronic acid transferase (UDP-GAT)
1% sulfertransferase/methyltransferase/acetyl transferase

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20
Q

phase 1 metabolism

A

functionalisation/activation of drugs
often oxidative
most important enzymes are CYP

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21
Q

phase 2 metabolism

A

enzyme families involved un conjugation for detoxification and/or excretion
important enzymes are UDPGTs and GSTs
each enzyme usually metabolises several drugs of similar structure

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22
Q

xanthine oxidase

A

primary metabolic enzyme involved in DNA/RNA base metabolism

metabolises caffeine, theobromine, theophylline

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23
Q

list phase 1 reactions

A 
oxidation (by CYP or mixed function oxidases)
hydrolysis
hydration
isomerisation
dethiacetylation
reduction
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24
Q

where are CYP enzymes found

A

in endoplasmic reticulum as they are hydrophilic so will dissolve in the membrane
they will metabolise hydrophobic drugs

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25
Q

requirements of CYP reactions

A

NADPH
O2
NADPH-CYP-reductase
more selective oxygenases for steroids due to specific substrate selectivity (found in mitochondria)

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26
Q

most common oxidative reaction

A

hydroxylation

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27
Q

selectivity in reactions

A

stereoselectivity - enzymes stereoselective so only one isomer produced
regioselectivity - specific carbon is hydroxylated and enzyme dependent (e.g. aromatic ring converted to phenol)

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28
Q

oxidation of CYP enzymes

A

they oxidate their prosthetic haem group, which chanes depending on the point in the cycle
reaction requires air, NADPH and reductase enzyme
enzyme generates highly reactive chemical species and suppressed the reactions which are not required
H+ from NADPH is fed into the reaction by the auxiliary enzyme

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29
Q

haem co-factor

A

non-covalently bound to the enzyme and its reactivity depends on iron ligands; the ligand can be o2, peroxide or left vacant

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30
Q

what is a superfamily

A

enzymes that catalyse a similar type of reaction and related by homology or identity

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31
Q

what is homology

A

same amino acids

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32
Q

definition of identity

A

same amino acids in sequence

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33
Q

glucuronidation

A

removes glucophiles

34
Q

Gunn rat

A

does not have the glucuronic acid transferase enzyme

35
Q

glucuronides

A

90% of phase 2 metabolites are glucuronides
they rely on the weight of conjugates in order to be excreted via the bile duct
if the conjugate results in an uncharged molecule, it is now water soluble and can be renally excreted/filtered

36
Q

nucleophiles removed by glucuronidation

A

O, N, S, C-
all have lone pairs
N and O are a result of phase 1 metabolism and are rarely found in drugs in this form

37
Q

b-D-glucose to UDP-glucuronic acid

A

OH group phosphorylates
UDP-P reacts and becomes biological leaving group with inversion
molecule oxidised twice
forms UDP-glucuronic acid

38
Q

UDP-ga leaving groups

A

alpha structure so leaves with inversion during the reaction, forming b-D-glucuronidase conjugate
different to endogenous formation which strips off glucuronidase and is excreted in faeces

39
Q

types of cyp reaction

A 
aromatic hydroxylation
aliphatic hydroxylation
aliphatic dealkylation
oxidative deamination
alcohol oxidation
epoxidation
herteroatom oxidation
dehalogenation
reduction
40
Q

aromatic hydroxylation

A

most common reaction, position of hydroxyl group depends on specific enzyme and drug

41
Q

aliphatic hydroxylation

A

stereoselective due to chiral centre
position and chirality of hydroxyl group depends on specific enzyme and drug
reaction results in specific stereoisomer

42
Q

oxidative deamination

A

leaving group is an amine

43
Q

alcohol hydroxylation

A

additional OH group added
water then eliminated
leaves methyl with H and =O bonds

44
Q

epoxidation

A

epoxide group hydrolysed to two OH groups

45
Q

epoxides

A

hydrolysed to diol by epoxide hydrolase

epoxides are electrophiles and their metabolites are highly reactive

46
Q

heteratom oxidation

A

addition of oxygen to N, O, S, P

47
Q

dehalogenation

A

oxygen added to same bond as halogen

halogen is leaving group and oxygen double bond

48
Q

reduction

A

less common and often involve heteroatoms

49
Q

factors affecting CYP metabolism

A

age, sex, hormones, genetics, polymorphisms, metabolic rates

50
Q

modelling of CYP enzymes

A

using x-ray crystal structures

51
Q

external factors affecting metabolism

A

diet, exercise, cooking methods, alcohol, smoking, co-administration of drugs, exposure to drugs/solvents/xenobiotics/pollutants, diseases

52
Q

what is the duration of a short term effect

A

hours

53
Q

what is the duration of a medium term effect

A

days/weeks/months

54
Q

what is the duration of a long term effect

A

years

55
Q

what is a perpetrator

A

the drug that takes priority when two administered drugs compete for the same enzyme

56
Q

what is a victim

A

the drug that does not get metabolised when two substrates compete for the same enzyme
can build to toxic levels

57
Q

phase 2 metabolism

A

detoxifies a drug or metabolite

allows excretion by adding a water-solubilising group

58
Q

types of phase 2 reaction

A 
glucuronidation
glutathione conjugation
amino acid conjugation
sulfation
acetylation
methylation
59
Q

what phase 2 process acts on nucleophiles

A

gluturonidation

60
Q

what phase 2 process acts on electrophiles

A

glutathione conjugation

61
Q

what is glucuronidation

A

addition of glucuronic acid (electrophile) to nucleophiles (lone e- pair and negative charge)

62
Q

common nucleophiles for glucuronidation

A 
OH groups
phenols
SH groups
carboxylate groups
amines
63
Q

where are UDP-GTs found

A

in ER membrane
for water solubilisation of hydrophobic CYP products
in tissues in liver, skin, intestines, kidney, lung, adrenals and spleen

64
Q

weight of drugs excreted in urine

A

<200Da

65
Q

enterohepatic circulation

A

drugs >200Da excreted in bile but can be recycled due to presence of b-D-glucuronidase
circulation can salvage important biochemicals
increases half life due to removal of glucuronic acid and reabsorption of drug
extends therapeutic effect but can increase toxicity

66
Q

what is Gilbert’s syndrome

A

common UGT deficiency
recessive
inefficient breakdown of bilirubin after breakdown of RBCs
can cause cyclical rise in bilirubin levels
mild symptoms can cause jaundice

67
Q

4 drugs affected by Gilbert’s syndrome

A

paracetamol
irinotecan
indinavir
atazanavin

68
Q

summary of UGTs

A

catalyse the transfer of glucuronic acid onto nucleophilic groups
many UGTs with overlapping substrate specificity

69
Q

function of glutathione

A

maintains reducing environment
protects against radicals and reactive oxygen species
reacts with electrophiles and detoxifies them

70
Q

GST superfamilies

A

cystolic
microsomal
mitochondrial

71
Q

glutathione and epoxides

A

SH group on glutathione is deprotonated to increase its reactivity
becomes S- which reacts with epoxide bond
oxygen on epoxide becomes protonated

72
Q

conjugate addition

A

occurs with e- deficient electron bonds (double bonds)

S- attaches to carbonyl group and forms an enolate intermediate

73
Q

1,6-conjugate addition

A

glutathione reacts during 1,6-conjugate addition and the reaction restores aromaticity
raction is highly favourable due to production of a stable aromatic

74
Q

conversion of metabolites to mercapturates

A

occurs in liver and kidneys
results in negatively charged mercapturate
involves sequential removal of glutamyl and glycyl residues
products are excreted in urine

75
Q

cytotoxic drugs in chemotherapy

A

highly electrophilic drugs
metabolised by GST enzymes
polymorphisms in GST drugs dictate success rate of drugs

76
Q

how is UDPGA formed

A

glucose converted to glucuronic acid to UDPGA

77
Q

components of glutathion

A

glu, cys, gly

joined by gamma bonds

78
Q

high affinity drugs

A

does not dissociate well from receptors - so undesireable

receptors can become desensitised if drugs are attached for too long

79
Q

reactive part of GST

A

lysine on GST reacts with toxic electrophiles

lysine has an NH2 group that gets protonated to NH3+

80
Q

methylation

A

catalysed by enzyme transferase with co-factor S-adenosylmethionine

81
Q

sulfation

A

uses co-factor PAPs
forms SO3- which can be renally eliminated
reaction occurs frequently with phenols

GI (21 decks)

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