PharmPK Discussion - Blood partitioning

• On 13 Apr 2015 at 13:08:24, satya jadhav (satyawanjadhav.-at-.gmail.com) sent the message
  

  
  Dear All,
  
  We have a compound having high blood/plasma ratio when dosed orally in vivo in preclinical species.
  The blood/plasma ratio was found to be as high as ~20 and was concentration-dependent. At higher
  doses and concentrations, the partitioning into blood cells appear to be saturated and blood/plasma
  ratio decreased to as low as ~2 to 3. The intravenous PK profile in blood but not in plasma (rats)
  exhibits a plateau at earlier time points ( upto 2h post dose) after which it follows
  monoexponential decline. The plasma concentrations shows biexponential decline with initial rapid
  distribution phase (probably due to rapid distribution to blood cells).
  
  A similar concentration dependent partitioning into blood cells was observed in an in vitro assay
  using human blood.
  
  We plan to use whole blood matrix (instead of plasma) for quantification of compound and subsequent
  PK assessments further during development path.
  
  I would highly appreciate if experts could help in getting answers to my questions as below.
  
   1. Can anyone provide more understanding  on concentration dependent blood cell partitioning and
  its implications on further development of the compound?
  
  2. Which matrix (blood vs plasma concentration) needs to be considered for risk assessment of
  liabilities like DDI due to CYP inhibition/induction?
  
  3. Are there any specific toxicity parameters (apart from those mentioned by Peter Hinderling in
  Pharmacol Review) we need to monitor for this compound ?
  
  Thanks
  
  Regards
  
  Satya
  
  

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