hello everyone
I have performed a dose acceleration experiment But I got linear plasma profile However There was a significant decrease in the liver and kidney concentration of the drug when normalized to the dose ( highest dose got the lower value of dose normalization ) and note worthy that is the drug is hepatically eliminated
please I need help is this possible
It appears that you may have an actively excreted cmpd that saturates the transporter with increased dose. Have you measured the fraction unbound in plasma? You might get a better assessment of this if you calculate a Kp,u,u or Cunbound, tissue/Cunbound, plasma.
Further to the comment above you may be interested in the following papers:
> Drug Disposition Classification Systems in Discovery and Development: A Comparative Review of the BDDCS, ECCS and ECCCS Concepts. Camenisch GP. Pharm Res. 2016 Nov;33(11):2583-93. Review
> New IVIVE method for the prediction of total human clearance and relative elimination pathway contributions from in vitro hepatocyte and microsome data. Riede J, Poller B, Umehara K, Huwyler J, Camenisch G. Eur J Pharm Sci. 2016 Apr 30;86:96-102
> Current In Vitro Methods to Determine Hepatic Kpuu: A Comparison of Their Usefulness and Limitations. Riede J, Camenisch G, Huwyler J, Poller B. J Pharm Sci. 2017 Sep;106(9):2805-2814
Question:
Is there albumin amiloriation in hepatic synthesis?
If answer is positive, please to measure albumin before the drug's sample
Let's to make the following: Css= steady state of drug concentration or trough concentration; Ds= standard deviation; EXP= exponential function
Then, to calculate:
a) I=0,75((Normal albumin range)-(albumin measured))
b) C1=Css(2-EXP(-I))
c) C2=Css(I+EXP(-I))
If your drug concentration is in between (C1-C2)+/- 1DS, you have a non-linear model to plot. If not, there are several other reasons by which the experiment can't be elucidated
kind regards
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