Drug Discovery 5 Flashcards
what is the aim especially early on in the drug discovery process?
avoid DMPK failure during development
predict safe and effective dose regimens in humans
what 6 key areas does Pharma seek to optimise early on in the discovery process ?
bioavailability controlling CNS exposure metabolite identification clearance avoid drug-drug interactions
what does a drug have to be to be able to cross the BBB for CNS exposure but what can cause problems ?
it has to be lipophilic because the capillaries are continuous in the brain to prevent the entry of toxins
P-glycoproteins are the brains defence mechanism against lipophilic drugs- these proteins can pump the drug back into the lumen
how can polar drugs enter into the brain ?
they can only enter if there is a specific carrier for them
e.g L-DOPA is an amino acid which can enter the brain via carrier proteins
give an example where a drug couldnt cross the BBB was an advantage…
atenolol cannot cross the BBB like propranolol which was good because propranolol caused sleep disturbanes
how can P-glycoprotein susceptibility be determined?
using MDCK-MDR1 monolayers
these are cells are a standard tool to determine if a drug is a candidate for P- glycoprotein
like Caco-2 cells they are polarised so they have apical and basolateral surfaces
they carry Pglycoproteins recombinantly
the drug is applied to the top chamber at the apical surface and then the amount of drug which enters the bottom chamber can be determined and then this process of diffusion is carried out in the opposite direction-if the drug is P-glycoprotein substrate then it will be pumped back into the top chamber
useful at looking at bioavailabilty as well
what should the ratio efflux produce by comparing apical-to-basolateral with basolateral-to-apical diffusion be ?
1
if it isnt then it siggests the role of P-glycoprotein - this can be assessed by inhibiting P-glycoprotein with cyclosporin
why is it useful to understand the mechanism and sites of action of a drugs metabolism ?
may help identify active metabolites - complicate the pharmacokinetic-pharmacodynamic relationship
may help avoid risk of reactive and toxic metabolites -
what methods can be used to identify safety issues ?
in silico method combined with several liver microsome assays - this only removes the really obviously dangerous compounds
what is an active metabolite and what are the issues surrounding them ?
active metabolites are compounds which despite having been metabolised, end up being more active than parent drug - this can complicate dosing and can unbalance the relationship between pharmacokinetics and pharmacodynamics
what can be used to make predictions about active metabolites ?
knowing the structure- activity relationship of the drug
knowing the pharmacophore of the drug
these coupled with likely metabolic products
what is an extreme case of active metabolites ?
when candidate compound is inactive and is converted to an active drug in the body- this can be useful in improving absorption or distribution
e.g L-DOPA
if metabolites are reactive what can this cause ?
lead onto toxicity, immunogenic responses, mutations and tumour formation
for optimal clearance what does a drug need ?
low clearance and a suitable half life - cant be tested in humans
can only be tested in humans once it has reached clinical trials
what are the 2 stages of optimising clearance ?
stage 1 = identify the key elimination processes that control clearance
stage 2 = optimise these processes using animal and in vitro human models
