Some CNS measures are more dependent on the rise of the concentration than on the actual concentration. So if the concentration increases rapidly the ED50 may occur at a lower concentration compared to if the concentration increases more slowly. 

Hello,

When you say exposure, do you mean the administered dose or the concentration in the plasma/brain at EC50 measurement?  How are you measuring the concentration of the drug or drug metabolites in the plasma and brain (radiolabel?).  Is it likely that some (but not complete) metabolism occurs in the gut microbiota prior to absorption when the drug is given orally?  

The absorption profile can be very different depending on the route of administration resulting in differing Tmax, Cmax, AUC, half-life, etc., as well as gut microbiota impacting oral routes.

If I understand your question I can say it does. Oral/intraperitoneal/intraveous/ routs have same EC50 but the apsorption,metabolism, and as is said Tmax,  Cmax, AUC, half-life is different

Thanks for response (Lois A Haighton & Nikola M Stojanovic)

I am looking at concentration in plasma or brain at EC50 measurement and measuring the non-radiolabeled parent molecule

Efficacy (50%) can be achieved only after attaining threshold plasma or brain drug exposures.

When the exposure levels are achieved through any route of drug administered (at high doses through oral or high doses through subcutaneous) the exposure (drug conc.) is expected to remain similar at 50% efficacy.

But it is not the case with the CNS drug tested.. Why? Please explain

Well blood/brain barrier is not permeable to all drugs in same manner, so may be that is the highest conc. in brain that you can achieve. Try increasing the dose of compound but it might not work, also the plasma conc does not have to be the same as the brain cocn.

Could it be possible that the efficacy (is it in a behavioral test?) that you are observing is not entirely due to the parent? If any of the metabolites is also active and its formation is route dependent, you could get 50% efficacy at different brain or plasma concentrations (of parent) with different routes.

Supporting point ...Nisha Kuzhuppilly Ramakrishnan 

Thank you very much, the variability may be because of active metabolites formed. On this I will check.

So it can be inferred that different EC50 values with different route of dosing for same efficacy is possible when its metabolite is active.

For your information I am working with receptor occupancy assays in pre clinical animals using cold and hot tracers. Here efficacy reflects my receptor occupancy. 

Well it is important if the compound is metabolized but that does not change your EC50. If the metabolized compound is active (not compound alone) the dose of e.g 100 mg is gona give 50mg of active compound, that still points to the fact that EC50 is 100mg of nonactive compound. The ratio of adsorption and metabolism deepend on rout of administration and jet again if the EC50 is 100mg/kg that is the EC50 no matter what the rout of administration is! The phamracodinamic/kinetic parameters are different but the active dose is the same! 

And I still dont understand what are you asking? 

 Jagadeesh, how are you measuring the receptor occupancy?

Nikola, you are thinking of ED50. EC50 would be the concentration of the compound in plasma or brain at 50% receptor occupancy.

Oh yea right :) ED50. sry 

 Nisha Kuzhuppilly Ramakrishnan

Occupancy is calculated by considering the reduction of specific regional tracer levels  (compared to vehicle group) in animal group pre treated with test compound. 

Depending on specific to non specific tracer conc. ratio of vehicle group, any one method i.e ratio or specific binding or positive control method will be implemented to calculate RO

Initially tracer (receptor selective) optimization will be done for  treatment time and dose of tracer and also for specific and non specific receptor regions.

Cold tracer quantification is with LC-MS/MS and hot tracer is with LSC

Sorry, I didn't give in detail, hope you are aware of what I mean. If needed I can help you.

Thank you Jagadeesh. I was wondering if you were doing PET or SPECT imaging as that is my field :)

Jagadeesh Thentu

The receptor occupancy assay is different from efficacy assay. Here you cannot find the linear relation between drug concentration and % of occupancy.

As you aware the receptor-ligand interaction is leading by the law of mass action, i.e number of receptors being occupied = [ligand concentration / (ligand concentration + Kd)], therefore you have to check the KD value for your tracer and test item for a better interpretation of the data. For more details please find below appended article for your information (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3000649/#b29)

Better ask to Gopi sir, I think he is an expert in this field

But, I don't think the route of administration is really going to affect the % RO

I think method of  administration will affect  very much the level of the drug in the body, and the level of bio availability, usually,  of the the drug, eg: . I.V. is  the fastest to reach the target within short time. It will be followed by other type of injection like: IM , IP, etc.

Oral administration will come after  with less bio availability. 

I agree with you, professor  

But in his case, he found different efficacy (% RO) with different route of administration, although it’s similar plasma and brain concentrations.

Therefore, I think the deviation in the efficacy (% RO) may be not related to route of administration  

Yes,  route of administration will affect the efficacy surly which is also affected by lipid solubility (affect membrane crossing processes ), metabolism - its metabolites. all this is regarding PK.

         And  the receptor occupancy also affect the efficacy of a drug. if there is no optimum level of D-R  complexes, there will be no optimum efficacy (Sub maximal response).

If it is your observation that you got same plasma concentration of drug in Plasma or Brain with different routes, that indicates the CNS drug  has good lipid solubility, and its metabolism does not affect its BA. \

But you didn't get  the same efficacy that indicates we need to check for receptor occupancy (Drug - receptor Occupation) or our method how we are measuring the Drug - receptor Occupancy (specific regional tracer levels).

If it is your assumption that both plasma or brain Concentration levels of drug will be same with P.O & S.C which will give same ED50, that is wrong there may be vary depending of drug & its properties, here D-R complex formation, local environment around the receptor & cell  will come into the picture.

my  suggestion is just check your  technical problem (methodology) or else the above reasons may be responsible for your problem. but  any drug efficacy will be affected by Route of Drug Administration.

with my knowledge i want  to justified your problem

Some CNS measures are more dependent on the rise of the concentration than on the actual concentration. So if the concentration increases rapidly the ED50 may occur at a lower concentration compared to if the concentration increases more slowly. 

Generally that  the concentration of any drug after one dose at the 1/2 time of the drug will reach 50% of the level . Most drugs will follow first order kinetic in its accumulation After the second dosing Css of the the drug will be about 75%. After the third dosing of the the drug at  its T1/2 time , the Css  will reach  87.5%and so on.  Therefore, Css  depends mainly on two factors  T1/2 and dosing.  So it is easy to estimate the level of the drug at any time after taking in consideration drug binding, metabolism and clearance, so accumulation of  drug is not easy . and yoy have to often moniter it