Flashcards
Brain penetration
Cards in this deck (28)
- 1why do we need a blood brian barriermaintain stable internal fluid environment(for reliable synaptic communication between nerve cells)
-BBB sheilds CNS from circulating neurotoxins - 2name 5 routes of drug entry into brain1) directly by crossing BBB
2)entering CSF via choroid plexus
3)Passage across tightly sealed cells of arachnoid membrane
4)From CVO’s into adjacent brain tissues and CSF
5)Through nasal epithelia, along olfactory nerve and into olfactory lobe - 3name 7 transport routes accross the BBB1)cell migration
2) passive diffusion
3)carrier mediated efflux
4)carrier mediated influx
5)receptor mediated transcytosis
6) adsorptitive mediated transcytosis
7) TJ modulation - 4which 2ways can drugs cross the BBBBpassive diffusion, carrier mediated efflux
- 5name some tools used to study BBBin silico, CSF sampling, knockout mice, PET/MRI
- 6name 4 characteristics of endothelial cels which effect BBB influx1) tight junctions
2) transporters
3) multi drug resistance PGP
4) metabolism - 7name 3 characteristics of the drug which affect its influx1) lipid solubility
2) molecular size
3) PSA - 8what are monikas rules for brain penetratinMWT<425
logP 0-5
rotatable bonds <12
H bond donors <6
H bond acceptors <11
PSA <70 - 9how do you work out th eB:B ratioconc in brain/conc in blood
- 10what is good about the B:B ratiobroadly distingushes between penetrant and non penetratn molecules and quantifies the relative affinity of the drug for brain tissue against circulating blood
- 112 common misconceptions about B:B ratio1) the best compound is the one with the biggest B:B ratio
2) brain total conc is proportioanl to the effect- there is no link between brain conc and efficacy - 12how do you measue ISF concBlood Cu will determine
available drug in brain for
passively penetrant molecules
Assess non-specific binding
in brain and use Fubrain to correct
Cbrain derived from a PK expt. to
give Cubrain as an indirect
measure of ISF concentration
ISF=Cubrain = Cbrain x Fubrain - 13how do you calculate Fulike plasma protein binding assay, using semipermeable membrane with artifical CSF in one side and Control brain homogenate in the other
fu= area [artifical CSF]/area[brain] - 14how do you get ISF concMeasuring Fubrain and using this to correct
Cbrain in order to obtain Cubrain - 15what is receptor occupancy interms of PKthe in vivo direct translation in vitro potency (%binding) = the drug action.
most popluat surrogate for efficacy - 16is Fubrain consistent across species?yes
- 17what does B:B not reflect?PK and PD
- 18what is the receptor biophaseinterstitail fluid (ISF)
- 19what does blood unbound (Cu) measure?avaiable drug in brain for PASSIVELY penetrant molecules
- 20when looking at B:B ratio what else must be consideredfraction unbound (Fu)
drug coud have a high B:B ratio but very low Fu meaning hardly any can travel and bind to receptor - 21as a rule how much receptor density should be targeted90%
- 22how can drug action be estimated% binding= ([drug]/kd+[drug])X100
tRO%= (Cu brain/kd+ Cu brain) X100 - 23how are drugs desgined so that hey dont pass the BBB (3 things)1) more polar
2) increase surface
3) these characteristics also reduce non specific binding - 24what can happen as a result of designing drugs to stay out of the CNScompensatory rise in the free drug levels
- 25how do you calcualte concentration unbound in the brainCu brain = C blood X Fu blood
- 26what changes the assumed equilbrium between Cu blood = Cu brain?68 transporters in the BBB (efflux)
- 27what indicates that influx is involved in BBB penetrationif the in vivo ratio (B:B) is much higher than the in vitro ratio
- 28does maximum brain total concentration maximise in vivo potencyno
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- Flashcards on Brain penetration, created by Zena Dodds on 07/04/2019.
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- Zena Dodds
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