I am doing dose acceleration study in mice, I used 0.16mg,1mg,5mg dose Iv bolus dose and this is what I got :
same CL,Ke
higher t1/2 with the lowest dose ( 0.16mg/kg) ~~4.5h
while the 1mg and 5mg/kg showed t1/2~~3h
higher Vd also in the lowest dose ~~0.6l/kg while the other doses was ~~0.4 in both
Dose normalized AUC was 15 ng/ml.h/mg/kg with 0.16mg/kg and 10 ng/ml.h/mg/kg in both of the other doses
Dose normalized C max showed not much of differences ( 1838,2978,2286 with 0.16,1,5 mg/kg respectively )
the liver concentration normalized to the dose was much lower with the higher Dose
Im really confused by the results and the only thing Im considering right now is the uptake transporters saturation ???
You need to be more clear and detail. I read your question three times and I could not understand it .
Mr.Amin thank you very much for considering my question I really need help
I gave a drug in 0.16mg,1mg,5mg/kg in IV bolus Dose to FVB mice WT and then chased the blood concentration at 0,5min ,30min,1,2,4,6,10,24h
and then collected tissue at 24h
what I got is a superimposable concentration-time profile of the the three dose however the tissue concentration when normalized to the Dose was significantly decreased with higher doses
normally if the drug follow linear pharmacokinetics the concentration-time profile of the three dose should not change when normalized to the dose and the same thing goes for the tissue concentration or what do you think
also I would like to mention that the variation between the mice was very very low
Dose acceleration has not any meaning. This was the first issue in understanding your question. After reading your second message where you describe increasing the dose of a drug I have these comments (hoping they may be useful):
- What you find in blood does not necessarily correlate with findings after "tissue collection" at 24 h. Then it is tricky to compare parameteres that cannot be directly compared.
- If you show the data in blood with time and drug concentration we can provide you our thoughts. Apparently what you interpret has a pitfall because in your interpretation you apparently are mixing things that cannot be directly compared.
- Without the data it seems that there is saturation as in almost any biological process. If you keep increasing the dose you reach saturation, i.e. concentration in tissue will not increase even if you increase the dose.
- Another issues (that may be more/less important depending in the tissue) is: potential enrichment of the drug and detection of metabolites instead of the "real" drug.
It is a very interested question.
I agree with the answer of Rafael
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