PharmPK Discussion - CYP IC50

• On 15 May 2013 at 11:00:08, Suresh P S (Suresh_PS.-at-.jubilantbiosys.com) sent the message
  

  
  Hi,
  
  Recently we have done a CYP IC50 study using 3A4 as a isoform using two
  different substrates (Midazolam and testosterone). Interestingly the IC50 values are 5.7 and >20 =B5M for Midazolam and testosterone, respectively for same compound.
  
  My question is why this much difference in IC50 for same compound and what is the mechanism behind this? It will be great if somebody can tell
  me some literature about this kind of phenomenon.
  
  Thanks and regards
  Regards
  Suresh
  

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• On 16 May 2013 at 15:39:16, "Pierce, David" (DPierce.-a-.shire.com) sent the message
  

  
  The following message was posted to: PharmPK
  
  Hi,
  
  The reason is that these substrates interact with CYP 3A4 at different
  sites. Please see the following articles by Steve Clarke et al for more
  details:
  
  1. Multisite kinetic analysis of interactions between prototypical
  CYP3A4 subgroup substrates: midazolam, testosterone, and nifedipine.
  Galetin A, Clarke SE, Houston JB.
  Drug Metab Dispos. 2003 Sep;31(9):1108-16.
  
  2.Quinidine and haloperidol as modifiers of CYP3A4 activity: multisite
  kinetic model approach.
  Galetin A, Clarke SE, Houston JB.
  Drug Metab Dispos. 2002 Dec;30(12):1512-22.
  
  3.Multisite kinetic models for CYP3A4: simultaneous activation and
  inhibition of diazepam and testosterone metabolism.
  Kenworthy KE, Clarke SE, Andrews J, Houston JB.
  Drug Metab Dispos. 2001 Dec;29(12):1644-51.
  
  Regards,
  
  David
  
  David Pierce, Ph.D.
  Senior Pharmacokinetics Director, Shire
  
  

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• On 17 May 2013 at 09:55:29, David Bourne (david.aaa.boomer.org) sent the message
  

  
  The following message was posted to: PharmPK
  
  Dear Suresh,
  
  This is not unusual as there are two binding mode/site in CYP3A4 and
  both testosterone and midazolam (structurally unrelated) do bind
  differently. If your test compound (inhibitor) is competing for one
  substrate may not be compete with other with same affinity or avidity
  and that can give different values with two structurally different
  substrate (probe). That is the reason FDA too recommend to evaluate your
  compound by using "Recommend use of 2 structurally unrelated CYP3A4/5
  substrates for evaluation of in vitro CYP3A inhibition". If the drug
  inhibits at least one CYP3A substrate in vitro, then in vivo evaluation
  is warranted.
  
  Hope I answered your query!
  
  Regards
  Zainuddin
  
  

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