PharmPK Discussion - High inert metabolite concentrations in humans

• On 5 Apr 2012 at 08:57:56, Clinical Pharmacology (clinical.pharmacology.-at-.yahoo.com) sent the message
  

  
  Hello All:
  
  We have tested a drug for the first time in humans and found something that was
  not seen in the animal species. The AUC of the drug's pharmacologically inactive
  metabolite (M1) is higher than that of the parent. In other words, the M1:Parent
  ratio across different dose groups is approximately 1.5. It poses the obvious
  questions - why subject humans to high concentrations of an pharmacologically
  inert molecule, the possibility of more DDIs, the potential for toxicity from
  the metabolite etc.
  
  Can someone provide me examples of any other marketed drugs in which this
  phenomenon was seen? It would help me look into how they tackled these issues.
  
  Thanks
  

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• On 5 Apr 2012 at 14:11:32, "Michael B. Bolger" (bolger.-at-.usc.edu) sent the message
  

  
  The following message was posted to: PharmPK
  
  Regarding the question about inactive human metabolite AUC being higher than the
  parent. Check out 5-amino-salicylic acid (mesalamine). It is metabolized by
  N-acetyltransferase-1 (NAT1) to the inactive N-acetyl-5-amino-salicylic acid and
  depending on the subject (fast or slow acetylator) the M1:parent Cmax ratio
  varies from 0.6 to 5.8.
  
  Mike
  
  * *
  Michael B. Bolger, Ph.D.
  Chief Scientist
  

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• On 5 Apr 2012 at 21:05:38, (Ttarnowski1.-a-.aol.com) sent the message
  

  
  Regarding the question about inactive human metabolite AUC being higher than the
  parent, I don't think that it is particularly unusual.  The circulating levels of
  mycophenolic acid glucuronide are much higher than the levels of active mycophenolic acid
  itself.  During drug development the inactive glucuronide was typically determined as well
  as the active species because it was a potential source of the active species.
  
  -Tom
  
  Thomas Tarnowski, Ph D.
  ttarnowski1.-at-.aol.com
  

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• On 8 Apr 2012 at 10:15:48, Jagannath Kota (jagannath.kota.-a-.gmail.com) sent the message
  

  
  Hi, appears to be a case requiring significant consideration. Is the molecule subject to
  extensive first pass extration. Is it possible to evaluate othe routes of administration,
  to overcome in case of FPE, regards, jagannath
  

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