lecture 6b Flashcards
what does hepatic clearance depend on
- the speed + volume of blood that enters the liver ‘Q’
- fraction of the drug not bound to the protein ‘fu’
why does hepatic clearance depend on Q
bc the hepatic blood flow is a measure of how efficiently drugs are carried to the liver
why does hepatic clearance depend on ‘fu’
bc hepatocytes can only access free + unbound drug molecules
what is EH
extraction ratio
measure of how efficiently a drug is removed from the body
extraction ratio equation
( fu x Clint ) / QH + fu x Clint
what is ClH
hepatic clearance
what is the hepatic clearance equation
QH x fu x Clint /
QH + fu x Clint
what is QH
hepatic blood flow
what is fu
fraction of unbound drug
unbound to a protein
it is free
what is Clint
intrinsic clearance
a higher Qh value means a lower (look at the equations)
EH value
when the intrinsic clearance is low,, a high hepatic blood flow leads to a
low extraction ratio
when the intrinsic clearance is high,, hepatic clearance increases in proportion to
hepatic blood flow
what does gene polymorphism allow
it allows hepatic gene makeup to be found between patients
what determines the rate of drug delivery to the liver
the rate at which blood is delivered to the liver
aka the net hepatic clearance of the drug depends on blood flow
what does a high intrinsic clearance value mean
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
what does a low intrinsic clearance value mean
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
what is the body comprised of
its comprised of many compartments
drugs can choose to hide in any compartment but may prefer one over another
why is knowing which body compartment drugs prefer important
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
after an injection,, many drugs distribute themselved to highly perfused organs,, name some
lungs
kidney
brain liver
what is half life,, t1/2
amount of time for the drugs conc in plasma to decrease by 50%
what does half life depend on
it depends on the rate constant ‘k’
t1/2 equation
0.693 x ( vol distribution c clearance )
what are the 2 types of half life
distribution half life
elimination half life
what is t1/2a
distribution half life
amount of time required for the conc of drug in the plasma to decrease by 50% in the distribution phase
what is t1/2b
elimination half life
amount of time required for the drugs conc in the plasma to decrease by 50% in the elimination phase
what is meant by distribution
movement of drug between the intravascular and extravascular compartments
what is an example of an intravascular compartment
blood
plasma
what is an example of an extravascular compartment
intracelullar + extracellular
fluid in the cell and outside the cell
aka distribution is mostly seen between
fluids in the body!!
intravascular + blood and plasma
extravascular + fluid in and out the cells aka intraceullular and extracellular
in 1 compartment of the body,, what equilibrium can the drug be in
either bound to a protein or free
aka free form or protein bound
whats VD
volume distribution
whats is volume distribution
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
equation for VD aka volume distribution
mass / concentration
this also equals volume
what does a higher VD aka volume distribution value mean
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
higher VD means
a higher dose is needed
what does a low VD aka a low volume distribution value mean
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
excretion/elimination and mass balance
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
why is biliary excretion performed
to understand the drug + its metabolites excretion via bile
what does biliary excretion show
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
how can we see the distribution of a metabolite
- 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
what is a metabolite
an intermediate or a product of metabolism
how can we assess tumour metabolism in in vivo studies
trace stable isotopes
advanced analytical technique: LC-MS
LC-MS electronspray ionisation
ideal method in the identification, and structure analysis of drug metabolites
as it is very sensitive + efficient
describe metabolite identification software and what it does
it screens all the ion chromatographs of expectedd metabolites + reveals possible metabolic reactions + relates them to certain changes of masses in tested drugs
what accounts for 10% of preclinical toxicology
developmental and reproductive toxicology
DART
what does DART stand for
developmental and reproductive toxicology.
drugs can affect the reproductive system in desirable and unwanted ways. what are they
desired : hormonal contraception
unwanted: side effect (antidepressants or thalidomide)
what substances cause birth defects
thalidomide
teratogens
