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Drug Metabolism Flashcards

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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
requirements of CYP reactions
NADPH O2 NADPH-CYP-reductase more selective oxygenases for steroids due to specific substrate selectivity (found in mitochondria)
26
most common oxidative reaction
hydroxylation
27
selectivity in reactions
stereoselectivity - enzymes stereoselective so only one isomer produced regioselectivity - specific carbon is hydroxylated and enzyme dependent (e.g. aromatic ring converted to phenol)
28
oxidation of CYP enzymes
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
29
haem co-factor
non-covalently bound to the enzyme and its reactivity depends on iron ligands; the ligand can be o2, peroxide or left vacant
30
what is a superfamily
enzymes that catalyse a similar type of reaction and related by homology or identity
31
what is homology
same amino acids
32
definition of identity
same amino acids in sequence
33
glucuronidation
removes glucophiles
34
Gunn rat
does not have the glucuronic acid transferase enzyme
35
glucuronides
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
nucleophiles removed by glucuronidation
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
b-D-glucose to UDP-glucuronic acid
OH group phosphorylates UDP-P reacts and becomes biological leaving group with inversion molecule oxidised twice forms UDP-glucuronic acid
38
UDP-ga leaving groups
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
types of cyp reaction
``` aromatic hydroxylation aliphatic hydroxylation aliphatic dealkylation oxidative deamination alcohol oxidation epoxidation herteroatom oxidation dehalogenation reduction ```
40
aromatic hydroxylation
most common reaction, position of hydroxyl group depends on specific enzyme and drug
41
aliphatic hydroxylation
stereoselective due to chiral centre position and chirality of hydroxyl group depends on specific enzyme and drug reaction results in specific stereoisomer
42
oxidative deamination
leaving group is an amine
43
alcohol hydroxylation
additional OH group added water then eliminated leaves methyl with H and =O bonds
44
epoxidation
epoxide group hydrolysed to two OH groups
45
epoxides
hydrolysed to diol by epoxide hydrolase | epoxides are electrophiles and their metabolites are highly reactive
46
heteratom oxidation
addition of oxygen to N, O, S, P
47
dehalogenation
oxygen added to same bond as halogen | halogen is leaving group and oxygen double bond
48
reduction
less common and often involve heteroatoms
49
factors affecting CYP metabolism
age, sex, hormones, genetics, polymorphisms, metabolic rates
50
modelling of CYP enzymes
using x-ray crystal structures
51
external factors affecting metabolism
diet, exercise, cooking methods, alcohol, smoking, co-administration of drugs, exposure to drugs/solvents/xenobiotics/pollutants, diseases
52
what is the duration of a short term effect
hours
53
what is the duration of a medium term effect
days/weeks/months
54
what is the duration of a long term effect
years
55
what is a perpetrator
the drug that takes priority when two administered drugs compete for the same enzyme
56
what is a victim
the drug that does not get metabolised when two substrates compete for the same enzyme can build to toxic levels
57
phase 2 metabolism
detoxifies a drug or metabolite | allows excretion by adding a water-solubilising group
58
types of phase 2 reaction
``` glucuronidation glutathione conjugation amino acid conjugation sulfation acetylation methylation ```
59
what phase 2 process acts on nucleophiles
gluturonidation
60
what phase 2 process acts on electrophiles
glutathione conjugation
61
what is glucuronidation
addition of glucuronic acid (electrophile) to nucleophiles (lone e- pair and negative charge)
62
common nucleophiles for glucuronidation
``` OH groups phenols SH groups carboxylate groups amines ```
63
where are UDP-GTs found
in ER membrane for water solubilisation of hydrophobic CYP products in tissues in liver, skin, intestines, kidney, lung, adrenals and spleen
64
weight of drugs excreted in urine
<200Da
65
enterohepatic circulation
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
what is Gilbert's syndrome
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
4 drugs affected by Gilbert's syndrome
paracetamol irinotecan indinavir atazanavin
68
summary of UGTs
catalyse the transfer of glucuronic acid onto nucleophilic groups many UGTs with overlapping substrate specificity
69
function of glutathione
maintains reducing environment protects against radicals and reactive oxygen species reacts with electrophiles and detoxifies them
70
GST superfamilies
cystolic microsomal mitochondrial
71
glutathione and epoxides
SH group on glutathione is deprotonated to increase its reactivity becomes S- which reacts with epoxide bond oxygen on epoxide becomes protonated
72
conjugate addition
occurs with e- deficient electron bonds (double bonds) | S- attaches to carbonyl group and forms an enolate intermediate
73
1,6-conjugate addition
glutathione reacts during 1,6-conjugate addition and the reaction restores aromaticity raction is highly favourable due to production of a stable aromatic
74
conversion of metabolites to mercapturates
occurs in liver and kidneys results in negatively charged mercapturate involves sequential removal of glutamyl and glycyl residues products are excreted in urine
75
cytotoxic drugs in chemotherapy
highly electrophilic drugs metabolised by GST enzymes polymorphisms in GST drugs dictate success rate of drugs
76
how is UDPGA formed
glucose converted to glucuronic acid to UDPGA
77
components of glutathion
glu, cys, gly | joined by gamma bonds
78
high affinity drugs
does not dissociate well from receptors - so undesireable | receptors can become desensitised if drugs are attached for too long
79
reactive part of GST
lysine on GST reacts with toxic electrophiles | lysine has an NH2 group that gets protonated to NH3+
80
methylation
catalysed by enzyme transferase with co-factor S-adenosylmethionine
81
sulfation
uses co-factor PAPs forms SO3- which can be renally eliminated reaction occurs frequently with phenols

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