PharmPK Discussion - Substrate inhibition of metabolism

• On 23 Jul 2013 at 08:17:13, MJ sent the message
  

  
  Dear all,
  When I read some textbook on PK, there are some views that really confusing me.  Would you please
  feel free give your comments to specify them?
  
  2)       One of the reasons for “sustained or elevated exposure at the beginning and the declining
  for conc. vs t profile for IV administration” is “substrate inhibition of metabolism during the
  initial phase”.  I cannot understand the substrate inhibition of metabolism well herein.
  
  Any comments on these views will be highly appreciated.
  
  Thanks in advance,
  MJ
  
  

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• On 23 Jul 2013 at 11:03:16, Masoud Jamei sent the message
  

  
  Hi MJ
  
  Hans gave a very good explanation to your other question and I won’t be able to match that level but
  try explaining it based on my understanding.
  
  As you know some drugs can inhibit (reduce) enzymes activities. Now, if a drug inhibits the same
  enzymes that contribute to its elimination then substrate inhibition of metabolism happens.
  
  This inhibition can happen for different reasons, e.g. negative co-operatively or time-dependent
  inhibition which both can cause non-linear elimination.
  
  When you give an IV dose, the level of drug concentration at the beginning is high as a result the
  level of inhibition is high so elimination is low and the drug level is sustained in the body.
  
  When gradually the drug level goes down the level of inhibition goes down as well which speeds up
  the elimination process so you have a faster decline in the concentration level.
  
  Hope this helps.
  
  Regards
  
  Masoud
  
  

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• On 23 Jul 2013 at 13:04:01, Ravi Kumar sent the message
  

  
  Dear Dr. Masoud,
  Thanks for nice explanation.
  One query- If TDI is involved, can elimination increase as parent concentration reduces at later
  time points ?
  Thanks.
  Regards.
  Ravi
  
  

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• On 24 Jul 2013 at 10:26:01, Masoud Jamei sent the message
  

  
  Dear Ravi
  
  Yes that can happen for TDI as well. As the substrate concentration goes down the level of
  inhibition reduces and as a result elimination goes up. Of course the initial question was related
  to auto-inhibition but this is the same when a TDI acts on a victim drug.
  
  Regards
  Masoud
  
  

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