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Drug Metabolism Flashcards

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1
Q

what does adme stand form and what is it the basis of

A

absorption (drugs ability to pass through barriers)
distribution (how the drug is distributed and its prepensity to accumulate in certain tissues or organs)
metabolism
excretion (rate at which the drug is clear from the body)

basis of pharmacodynamics

Order of abs->dist-> meta or abs->met-> dis dependes on where drug is absorbed (e.g. if inhaled is distuvted first from lung in blood then metabolized. If oral thrn intestine ->liver metabolized first)

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2
Q

where does the majority of drug metabolism occur

A

in the liver, however most cells and tissues can also contribute

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3
Q

what is the path of an oral drug

A 
stomach 
intestine 
hepatic portal system 
liver 
bile 
gall bladder 
intestine 
stool
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4
Q

what is first pass metabolism

A

when a drug passes through the liver and is metabolised on its first time through the liver

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5
Q

what is the function of metabolites of drugs

A

these can have same pharmacological action as parent molecule or can have additional actions

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6
Q

what are pro drugs

A

drugs that are inactive until they are metabolised into metabolites

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7
Q

what is the role of kidneys in drug metabolism

A

take drug from blood
metabolise it
excrete it in urine

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8
Q

what is pharmacodynamics

A

what the drug does to the body - the effect on the body

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9
Q

what is pharmacokinetics

A

what the body does to the drug- how it is metabolised, its distribution and its excretion

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10
Q

in a blood concentration curve what is the incline of the slope

A

absorption

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11
Q

in a blood concentration curve what is the decline of the slope

A

elimination

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12
Q

in a blood concentration curve what is Cmax

A

point of highest blood concentration in the blood

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13
Q

in a blood concentration curve what is t1/2

A

half life = time at which is drug has lost half its mac concentration

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14
Q

in a blood concentration curve what is Cmin

A

lowest concentration of drug in the blood

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15
Q

in a blood concentration curve what is the area under the curve

A

overall exposure to the drug

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16
Q

in a blood concentration curve what are Tmax and Tmin

A

Time at which Cmax and Cmin are achieved

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17
Q

what is xenobiotic metabolism

A

chemical transformation by a biological system usually via drug metabolising enzymes which converts lipophilic compounds into more readily excrete hydrophilic metabolites

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18
Q

what are the basic processed in the three phases of metabolism

A 
1= modification (oxidation, reduction, demythylation, hydrolysis) 
2= conjugation (methylation, sulphation, acetylation)
3= excretion, modification (effluc from the cell, modification same as phase 1)
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19
Q

what is exposed in phase 1

A

functional group on the compound being modified

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20
Q

what is conjugation

A

the addition of a chemical moiety to the functional groups exposed in phase 1

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21
Q

what are the main enzymes in phase 2

A

UGTs (UDP glucuronyl transferases) and STs (sulphur transferases)

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22
Q

what are phase 3 transporters found

A

on surface where the inside meets the outside- e.g. intestine, hepatocytes, kidney, BBB

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23
Q

which phase of metabolism is catabolic and which is anabolic

A

phase 1 catabolic

phase 2 anabolic

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24
Q

generally does metabolism make things more or less polar

A

more- makes it easier to excrete

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25
what does phase 1 do in terms of nucleophillic and electrophilic molecules
phase 1 makes nucleophilic molecules such as hydroxyl, nitrogen or sulphate moiety or it can make a substance electrophillic either way it makes it less lipophillic and allows it to be conjugated
26
name 3 other sites where metabolism happens
kidneys, lungs, plasma
27
what happens in drug overdoses
phase 1 makes lots of highly reactive intermediates phase 2 enzymes are overwhelmed intermediates accumulate and cam cause damage
28
how do the drugs/ chemicals or xenobiotics that need to be metabolised affect this metabolism
bind to nuclear receptors (PXR CAR and AhR which act as sensors of xenobiotics in the cell) these dimerise with binding partner (RXR and ARNT) this binds to responive elements in a series of genes encompassing the components of phases 1,2 and 3 - upregulating them induce the activity or expression of of components of metabolism, increasing excretion of the drug as drug levels decrease so too do these signals
29
what components affect the cellular adaptive response system
``` genetic changes (polymorphisms) environmental factors (drugs, chemicals) ``` why everyone responds to a different drug in a different way
30
what is functionalisation
(phase 1 metabolism) | reaction to produce or uncover functional group for phase 2
31
give examples of reactions that happen in phase 1
oxidation, reduction, hydrolysis
32
what enzymes do 90% of phase 1 reactions
cytochrome p450s
33
what is flavin containing monooxygenase
membrane bound receptors high concs in liver uses the co factors NADPH and O2 to do N- and S- oxidation (oxidation at N and S atoms) not inducible
34
what is the main FMO in humans
FMO3
35
what does a polymorphism in FMO£ cause
smelly excretion of trimethylamine
36
what are cytochrome p450s
``` group of haem thioloate monoxygenases terminal oxidase (eletron acceptor) is an electron transfer system of the ER ```
37
what are the role sof p450s
steroid biosynthesis bile acid synthesis drug/ xenobiotic metabolism fatty acid metabolism
38
what is POR
p450 oxidoreductase- whats feeds p450s electrons from NADPH
39
where are p450s found
on ER
40
how are there allele p450s
as same sub family and protein only differing by individual amino acids or bases
41
what are pseudogenes
genes that used to have a function historically but have lost it due to genetic changes
42
how many forms of p450 in humans
57
43
what is the obligate donor to p450s
POR
44
which p450 is probs the most important for humans
cyp3a4/5
45
can p450s do lots of different reactions
yes with lots of different substrates | e.g. hydroxylation, demethylation, oxidation
46
what are the most activate enzymes in phase 2
``` transferases: glucuronyl t glutathione t sulphotransferases acetyl t methyl t ```
47
what are UGTs
``` UDP glucoronsyltransferases add on glucuronic acid (a sugar) membrane bound protein high conc in liver catalyse most common phase 2 reactions ```
48
what can induce UGTs
steroids, phenobarbitone
49
give examples of what UGTs can conjuate
ibruprofen, paracetamol, naproxen, lamotrigine
50
how are glucuronide conjugates excreted
in urine
51
what are sulphotransferases substrates
alcohol phenol cholesterol
52
what phase 2 enzymes are overwhelmed in paracetamol OD
UGT and SULT
53
where are n -acetyl transferases
liver
54
what does a polymorphic n-acetyl transferase mean
can have either slow or fast acting enzyme
55
what is glutathione
protective compound in the body used for the removal of potentially toxic electrophillic compounds reacts with eletrophiles to form less toxic conjugates
56
what can be metabolised by p450 into eletrophiles
drugs and pro carcinogens
57
what do glutathione transferases do
conjugate electrophiles to glutathione
58
what are the types of transporters
efflux/ export | uptake/ import (all either organic anion or organic cation)
59
why are transporters important for cancer drugs
as they can remove drug from cell e.g. paclitaxel and ABCB1 | to increase drug exposure need to get around the transporters
60
what happens if you inhibit or induce cyp450s
inhibit= higher drug concs in body (e.g. grapefruit) | induce- more excretion of drug
61
what do polymorphisms in genes for drug metabolising enzymes cause
increased or decreased enzyme activity: - poor metabolisers (can cause toxic levels of drug in body or mean it doesn't have effect as not activated) - ultra rapid metabolisers (may not get effect from drug or e.g. codein convert into too much morphine and od)
62
what are extensive drug metabolisers
have wild type/ normal drug metabolising enzyme activity
63
why might targeting p450 in cancer be helpful
as can find specific p450 in tumour and give drug activated by it so drug only active in tumour
64
why is it hard to test drug metabolism in mice
as have different p450s | trying to create mice model with human p450s
65
summarise the cellular adaptive response system
induction of enzymes and transporters via nuclear receptors to metabolised perceived drug targets
66
what are electrophiles
electron deficient (+ve/neutral) attracted to electron rich centre (made by reduction)
67
what are nucleophiles
electron rich (-ve/neutral) attracted to electron deficient environment (made by hydrolysis and reduction)
68
what element is found in the centre of p450s
iron (are haem thiolate monooxygenases)
69
what does *0 mean in a cyp450 allele
the wild type
70
what is the role of glutathione
conjugated to electrophilic compounds in phase 2 by GST
71
what can oltipraz do
inhibit cytp450s induce phase 2 enzymes less reactive products made, more of them mopped up prevents tumours associated with aflatoxin
72
do women and men respond to drugs the same
no

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