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drug discovery > lecture 6b > Flashcards

lecture 6b Flashcards

1
Q

what does hepatic clearance depend on

A
  • the speed + volume of blood that enters the liver ‘Q’
  • fraction of the drug not bound to the protein ‘fu’
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2
Q

why does hepatic clearance depend on Q

A

bc the hepatic blood flow is a measure of how efficiently drugs are carried to the liver

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3
Q

why does hepatic clearance depend on ‘fu’

A

bc hepatocytes can only access free + unbound drug molecules

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4
Q

what is EH

A

extraction ratio
measure of how efficiently a drug is removed from the body

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5
Q

extraction ratio equation

A

( fu x Clint ) / QH + fu x Clint

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6
Q

what is ClH

A

hepatic clearance

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7
Q

what is the hepatic clearance equation

A

QH x fu x Clint /
QH + fu x Clint

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8
Q

what is QH

A

hepatic blood flow

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9
Q

what is fu

A

fraction of unbound drug

unbound to a protein
it is free

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10
Q

what is Clint

A

intrinsic clearance

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11
Q

a higher Qh value means a lower (look at the equations)

A

EH value

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12
Q

when the intrinsic clearance is low,, a high hepatic blood flow leads to a

A

low extraction ratio

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13
Q

when the intrinsic clearance is high,, hepatic clearance increases in proportion to

A

hepatic blood flow

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14
Q

what does gene polymorphism allow

A

it allows hepatic gene makeup to be found between patients

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15
Q

what determines the rate of drug delivery to the liver

A

the rate at which blood is delivered to the liver

aka the net hepatic clearance of the drug depends on blood flow

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16
Q

what does a high intrinsic clearance value mean

A

it means the hepatic metabolism is very efficient at removing the drug from circulation

even tho the Qh is high,, EH doesnt drop by much

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17
Q

what does a low intrinsic clearance value mean

A

a high + speedy blood flow, Qh, doesnt have a strong positive effect on extraction ratio..

the clearance is just bad, no matter how fast the blood gets delivered to the liver

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18
Q

what is the body comprised of

A

its comprised of many compartments

drugs can choose to hide in any compartment but may prefer one over another

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19
Q

why is knowing which body compartment drugs prefer important

A

may help us gain info into their therapeutic potential

aka if it likes going to the brain maybe it can be used to help ppl with brain injuries etc

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20
Q

after an injection,, many drugs distribute themselved to highly perfused organs,, name some

A

lungs
kidney
brain liver

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21
Q

what is half life,, t1/2

A

amount of time for the drugs conc in plasma to decrease by 50%

22
Q

what does half life depend on

A

it depends on the rate constant ‘k’

23
Q

t1/2 equation

A

0.693 x ( vol distribution c clearance )

24
Q

what are the 2 types of half life

A

distribution half life

elimination half life

25
Q

what is t1/2a

A

distribution half life
amount of time required for the conc of drug in the plasma to decrease by 50% in the distribution phase

26
Q

what is t1/2b

A

elimination half life
amount of time required for the drugs conc in the plasma to decrease by 50% in the elimination phase

27
Q

what is meant by distribution

A

movement of drug between the intravascular and extravascular compartments

28
Q

what is an example of an intravascular compartment

A

blood
plasma

29
Q

what is an example of an extravascular compartment

A

intracelullar + extracellular

fluid in the cell and outside the cell

30
Q

aka distribution is mostly seen between

A

fluids in the body!!

intravascular + blood and plasma

extravascular + fluid in and out the cells aka intraceullular and extracellular

31
Q

in 1 compartment of the body,, what equilibrium can the drug be in

A

either bound to a protein or free

aka free form or protein bound

32
Q

whats VD

A

volume distribution

33
Q

whats is volume distribution

A

a pharmacokinetic parameter that represents a drugs tendency to remain in plasma or redistribute to other tissue compartments.

aka does it stay in the plasma or go to a different tissure compartment

34
Q

equation for VD aka volume distribution

A

mass / concentration

this also equals volume

35
Q

what does a higher VD aka volume distribution value mean

A

drug is distributed more to other tissues

it leaves the plasma more

it enters more extravascular compartments

a higher dose is needed to achieve the required plasma concentration

36
Q

higher VD means

A

a higher dose is needed

37
Q

what does a low VD aka a low volume distribution value mean

A

the drug prefers to stay in the plasma,, intravascular compartment.

a lower dose is required to achieve a required plasma conc

it doesnt distribute itself to other tissue compartments as much

38
Q

excretion/elimination and mass balance

A

in vivo mass balance studies provide info into the route a drug takes when eliminated + the conc of the drug in related materials

aka materials related to elimination such as expired air, urine + faeces

39
Q

why is biliary excretion performed

A

to understand the drug + its metabolites excretion via bile

40
Q

what does biliary excretion show

A

if the drug is absorbed + excreted from bile to faeces

if the drug isnt absorbed and is excreted by faeces right away

aka is the drug being absorbed or no

41
Q

how can we see the distribution of a metabolite

A
  • radioactivity detection : drug is localised on a chromatograph and mass spec is used to identify metabolites

C14 is used as its radioactive yet still safe and has a long half life,, it can also be easily added to the drug

42
Q

what is a metabolite

A

an intermediate or a product of metabolism

43
Q

how can we assess tumour metabolism in in vivo studies

A

trace stable isotopes

44
Q

advanced analytical technique: LC-MS

A

LC-MS electronspray ionisation

ideal method in the identification, and structure analysis of drug metabolites

as it is very sensitive + efficient

45
Q

describe metabolite identification software and what it does

A

it screens all the ion chromatographs of expectedd metabolites + reveals possible metabolic reactions + relates them to certain changes of masses in tested drugs

46
Q
A
47
Q

what accounts for 10% of preclinical toxicology

A

developmental and reproductive toxicology

DART

48
Q

what does DART stand for

A

developmental and reproductive toxicology.

49
Q

drugs can affect the reproductive system in desirable and unwanted ways. what are they

A

desired : hormonal contraception
unwanted: side effect (antidepressants or thalidomide)

50
Q

what substances cause birth defects

A

thalidomide

teratogens

drug discovery (18 decks)

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