PharmPK Discussion - Mandatory in vitro drug profiling required

• On 6 Aug 2011 at 05:52:26, purna chandra rao (chandram00.aaa.gmail.com) sent the message
  

  
  Dear All Members,
  
  Do really mandatory of in vitro drug profiling with recombinant CYP450
  enzymes or is there any alternative method?
  
  If yes, will FDA give the clearance for it?
  
  Is recombinant CYP450 enzymes play important role in future too?
  
  Thanks and Regards,
  Chandram
  
  

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• On 8 Aug 2011 at 10:04:35, Bernard Murray (Bernard.Murray.-a-.gilead.com) sent the message
  

  
  The following message was posted to: PharmPK
  
  Chandram,
  
  No, P450 reaction phenotyping is not "mandatory" - but it often forms part of the effort
  to provide e.g "...information on the... metabolism... of the drug, if known." [IND 21CFR
  312.23 8(i)].
  
  If metabolism contributes a substantial part to the clearance of your drug then
  understanding the enzymology of metabolism allows rational prediction of the drug
  interaction potential (interaction with other drugs, diet, other environmental factors and
  host genetics).  If you can show that the majority of clearance is through excretion or
  through metabolism via non-P450 pathways then you could make a strong argument that P450
  reaction phenotyping would not be required (instead you would work to understand which
  transporters or which non-P450 enzymes are involved).
  
  Alternatives to the use of recombinant cytochrome P450 enzymes include:
  Examining the effects of enzyme-selective chemical inhibitors or antibodies on the
  microsomal metabolism of the drug.
  Correlation studies using activity-phenotyped microsomal fractions from multiple donors.
  
  Because of the difficulties in extrapolation of results obtained with recombinant enzymes
  it is often helpful to combine multiple techniques.
  
  Studies with recombinant enzymes are useful because the negative results are particularly
  important - if you don't see metabolism of your compound, but see good turnover of a
  positive control, then you can be reasonably confident that the enzyme will not play a
  significant role in the disposition of your compound.
  
  I hope that helps.
  
  All the very best,
  
  Bernard
  
  Bernard Murray, Ph.D.
  Senior Research Scientist, Drug Metabolism
  Gilead Sciences, Foster City CA
  
  

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