PharmPK Discussion - Variability from i.p. dosing in rat

• On 26 Aug 2011 at 14:53:51, Michael Cameron (cameron.aaa.scripps.edu) sent the message
  

  
  The following message was posted to: PharmPK
  
  I am hoping that someone might have a suggestion for factors that lead
  to high variability from i.p. dosing in rat. In the past we have had
  reasonable luck with i.p. administration in rat. Recently we started
  working with a new series of compounds that are yielding unbelievably
  large variation (e.g. 2 hr time point, n=8 dosed at 10 mg/kg i.p. = 6.6,
  6.1, 5.7, 5.3, 4.9, 0.7, 0.05, 0.01 micromolar plasma levels). The first
  5 are nicely grouped, but the last 3 are obviously different.  Results
  from additional time points are similar. Three compounds from this
  series have shown similar variability but structurally unrelated
  compounds are still giving reproducible results so I do not believe it
  is a technical error such as injecting into an organ and not into the
  i.p. space. The compounds are moderately soluble at neutral pH and I do
  not believe this is the source of the problem. I increased the volume of
  the dose from 0.5 ml to 2 ml but this did not help. The formulations
  were 5% DMSO/5% tween 80/90% water. I know tween 80 has been shown to
  have an inhibitory effect on some transporters but I would expect this
  to similarly affect all of the rats and not drastically increase
  variability. There was an oral arm to the study so all animals were
  fasted overnight and food was reintroduced one hour after dosing. The
  i.p. space drains via the lymphatic system into the intestine. Could
  differences in food intake have such a large affect for i.p. doses?
  Anything obvious that I am missing?
  
  Regards,
  Mike
  
  

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