PharmPK Discussion - Difference between Time Dependent Inhibition and Metabolism Dependent Inhibition

• On 26 Aug 2011 at 08:54:34, purna chandra rao (chandram00.-a-.gmail.com) sent the message
  

  
  Dear All,
  
  What is the exact difference between TDI Vs MDI (Time Dependent
  Inhibition Vs Metabolism Dependent Inhibition) while using Liver
  microsomes and recombinant CYPs?
  
  Thanks and Regards,
  Chandram
  
  

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• On 25 Aug 2011 at 21:37:08, David Bourne (david.-a-.boomer.org) sent the message
  

  
  Dear All,
  
  What is the exact difference between TDI Vs MDI (Time Dependent
  Inhibition Vs Metabolism Dependent Inhibition) while using Liver
  microsomes and recombinant CYPs?
  
  Thanks and Regards,
  Chandram
  
  

  Back to the Top

• On 26 Aug 2011 at 18:06:20, vijaya bhargava (vijayabhargava.k.-at-.gmail.com) sent the message
  

  
  The following message was posted to: PharmPK
  
  both are same essentially because either the time dependent inhibition
  or metabolism based inhibition is a cause of the metabolites that are
  formed as a process of metabolism of the parent compound under
  investigation by the liver microsomes or the recombinant cytochromes
  when NADPh is supplemented. This is alternative to a directly acting
  inhibitor where the IC 50 of  a compound shifts to a lower side when
  the enzymes are pre-incubated for a definitive time interval say
  30 min.
  
  

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• On 28 Aug 2011 at 20:24:39, "NADIGER, Vinayak" (vnadiger.at.formatherapeutics.com) sent the message
  

  
  The following message was posted to: PharmPK
  
  Dear Chandram,
  I am not an expert in this field. But I have read an article on
  autoactivation phenomenon. Can this be considered metabolism dependant
  inhibition?
  
  QUINIDINE AND HALOPERIDOL AS MODIFIERS OF CYP3A4 ACTIVITY: MULTISITE
  KINETIC MODEL APPROACH
  ALEKSANDRA GALETIN, STEPHEN E. CLARKE, AND J. BRIAN HOUSTON
  School of Pharmacy and Pharmaceutical Sciences, University of
  Manchester, Manchester, United Kingdom (A.G., J.B.H.); and Department of
  Mechanism and Extrapolation Technologies, GlaxoSmithKline, Welwyn,
  Hertfordshire, United Kingdom (S.E.C.)
  
  Regards,
  Vinayak Nadiger
  
  Vinayak Nadiger
  Senior Scientist
  Forma Therapeutics(Singapore)
  11,Biopolis Way ,Helios # 08-05
  Singapore 1386607
  
  

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• On 29 Aug 2011 at 12:28:39, krishna machavaram (machavaramk.-at-.gmail.com) sent the message
  

  
  Dear Chandram,
  
  By definition, TDI is a compound which demonstrates an increase in the
  extent of inhibition when it is incubated with the enzyme before
  addition of the substrate.
  
  In general, time dependent inhibition results from mechanism-based
  inhibition (due to irreversible covalent binding or quasi-irreversible
  non-covalent binding of a chemically reactive intermediate to the
  enzyme) and/or metabolite/product inhibition (due to reversible
  inhibition from a metabolite(s)).
  
  Hope this information is useful and you can find more details in the
  reference given below.
  
  Grimm et al., DMD 37, 1355-70, 2009
  
  Best regards,
  Krishna
  
  

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