lecture 6b

Question 1

what does hepatic clearance depend on

Answer 1

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

Question 2

why does hepatic clearance depend on Q

Answer 2

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

Question 3

why does hepatic clearance depend on ‘fu’

Answer 3

bc hepatocytes can only access free + unbound drug molecules

Question 4

what is EH

Answer 4

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

Question 5

extraction ratio equation

Answer 5

( fu x Clint ) / QH + fu x Clint

Question 6

what is ClH

Answer 6

hepatic clearance

Question 7

what is the hepatic clearance equation

Answer 7

QH x fu x Clint /
QH + fu x Clint

Question 8

what is QH

Answer 8

hepatic blood flow

Question 9

what is fu

Answer 9

fraction of unbound drug

unbound to a protein
it is free

Question 10

what is Clint

Answer 10

intrinsic clearance

Question 11

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

Answer 11

EH value

Question 12

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

Answer 12

low extraction ratio

Question 13

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

Answer 13

hepatic blood flow

Question 14

what does gene polymorphism allow

Answer 14

it allows hepatic gene makeup to be found between patients

Question 15

what determines the rate of drug delivery to the liver

Answer 15

the rate at which blood is delivered to the liver

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

Question 16

what does a high intrinsic clearance value mean

Answer 16

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

Question 17

what does a low intrinsic clearance value mean

Answer 17

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

Question 18

what is the body comprised of

Answer 18

its comprised of many compartments

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

Question 19

why is knowing which body compartment drugs prefer important

Answer 19

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

Question 20

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

Answer 20

lungs
kidney
brain liver

Question 21

what is half life,, t1/2

Answer 21

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

Question 22

what does half life depend on

Answer 22

it depends on the rate constant ‘k’

Question 23

t1/2 equation

Answer 23

0.693 x ( vol distribution c clearance )

Question 24

what are the 2 types of half life

Answer 24

distribution half life

elimination half life

Question 25

what is t1/2a

Answer 25

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

Question 26

what is t1/2b

Answer 26

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

Question 27

what is meant by distribution

Answer 27

movement of drug between the intravascular and extravascular compartments

Question 28

what is an example of an intravascular compartment

Answer 28

blood plasma

Question 29

what is an example of an extravascular compartment

Answer 29

intracelullar + extracellular fluid in the cell and outside the cell

Question 30

aka distribution is mostly seen between

Answer 30

fluids in the body!! intravascular + blood and plasma extravascular + fluid in and out the cells aka intraceullular and extracellular

Question 31

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

Answer 31

either bound to a protein or free aka free form or protein bound

Question 32

whats VD

Answer 32

volume distribution

Question 33

whats is volume distribution

Answer 33

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

Question 34

equation for VD aka volume distribution

Answer 34

mass / concentration this also equals volume

Question 35

what does a higher VD aka volume distribution value mean

Answer 35

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

Question 36

higher VD means

Answer 36

a higher dose is needed

Question 37

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

Answer 37

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

Question 38

excretion/elimination and mass balance

Answer 38

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

Question 39

why is biliary excretion performed

Answer 39

to understand the drug + its metabolites excretion via bile

Question 40

what does biliary excretion show

Answer 40

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

Question 41

how can we see the distribution of a metabolite

Answer 41

- 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

Question 42

what is a metabolite

Answer 42

an intermediate or a product of metabolism

Question 43

how can we assess tumour metabolism in in vivo studies

Answer 43

trace stable isotopes

Question 44

advanced analytical technique: LC-MS

Answer 44

LC-MS electronspray ionisation ideal method in the identification, and structure analysis of drug metabolites as it is very sensitive + efficient

Question 45

describe metabolite identification software and what it does

Answer 45

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

Question 47

what accounts for 10% of preclinical toxicology

Answer 47

developmental and reproductive toxicology DART

Question 48

what does DART stand for

Answer 48

developmental and reproductive toxicology.

Question 49

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

Answer 49

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

Question 50

what substances cause birth defects

Answer 50

thalidomide teratogens