PharmPK Discussion - GI toxic

• On 11 Jan 2012 at 19:26:04, pan yan (pyph2004.at.gmail.com) sent the message
  

  
  Hi all,
  
  Dose anyone have the experience of GI toxic? We want to give a rat BID
  oral dose for one compound at 200 mg/kg for 4 days, we don't know
  whether it could induce adverse effect to GI tract.  We once dosed 200
  mg/kg IP BID for 4 days and found no issue. Except that, we found the
  oral exposure of this compound was very low.
  
  thanks,
  
  Frank
  
  

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• On 12 Jan 2012 at 01:09:59, wangchangguang (chg-wang.at.hotmail.com) sent the message
  

  
  Hi Frank,
  
  I think it is depends on what kinds of solvent you use and the volume
  you dose, for a 300g rat, 1ml gavage is ideal , no more than 3ml.
  
   The oral exposure sometimes can be affected by the formulation of your
  comp. (Permeability and dissolution rate)
    a slurry or  a solution will give different exposure for some of the
  comp. but not all. I always try to formulate my comp. into solution.
  
  Thanks
  
  chang
  
  Department of Biochemistry
  UT Southwestern Medical Center
  5323 Harry Hines Boulevard
  Dallas, Texas 75390-9038
  
  Email:chg-wang.aaa.hotmail.com
  
  

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• On 12 Jan 2012 at 17:01:33, Sanjeev Thohan (sarxconsult.-a-.gmail.com) sent the message
  

  
  Hi Frank,
  
  you would need to know what the carrier vehicle is that you are using
  and not administer more than 10mL/kg. Sometimes you can hvae an additive
  iritant effet from the vehicle, so its better to use a very neutral
  excipient mix, if possible. IP dosing bypasses the upper GI and allows
  systemic exposure, as you know and will not  give you an assessment of
  the  GI risk at all.
  
  Do the physicochemical properties allow you to dose 10 mL/kg (20 mg/mL?)
  as a solution dose? In general terms, and there are obvious exceptions,
  a solution dose would give you the best opportunity for a
  bioavailability profile. Did you administer this compound IV?
  
  thanks,
  
  sanjeev
  SARX consulting.
  
  

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• On 15 Jan 2012 at 14:32:39, pan yan (pyph2004.-a-.gmail.com) sent the message
  

  
  Hi Sanjeev,
  
  Thanks for your response.
  
  We will use 2% Tween80 + 0.5% HPMC as vehicle for the PO study. Actually, it's a suspension
  at 20 mg/mL. We once dosed oral solution at 10 mg/kg and found almost no exposure, the IV
  PK profile is good for the compound.
  
  Anyway, we will decrease the oral dosage for the 3 day BID study since we have no idea
  about the GI toxic.
  
  Regards,
  Frank
  

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• On 16 Jan 2012 at 16:58:06, Sanjeev Thohan (sarxconsult.aaa.gmail.com) sent the message
  

  
  Thanks Frank,
  
  Have you done an intradoudenal instillation in surgically modified rats, its an
  alternative to the traditonal stomach instillation, also how about a heaptic portal
  infusion - yes it requires an IV formulation but you will get a really clear idea of
  hepatic extraction as well as exposure of your compound. Haing animals that have a jugular
  cannualtion can also facilitate early sampling times to capture a rapidly distributing or
  rapid elimination compound.
  
  sanjeev
  
  SARx Consulting.
  

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• On 19 Jan 2012 at 12:59:43, pan yan (pyph2004.aaa.gmail.com) sent the message
  

  
  Hi Sanjeev,
  
  Thanks for your very useful information. We are considering
  intradoudenal instillation and heaptic portal infusion methods, could
  you please provide any general guidelines for the two methods?
  
  Many thanks,
  
  Frank
  
  

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