PharmPK Discussion - Differentiating hepatic and GI metabolite

• On 27 Jul 2013 at 22:24:39, Mengyao Li sent the message
  

  
  Dear group,
  
  I have a general question confused me for a while. For example, Midazolam (MDZ) is a CYP3A
  substrate. I know the AUC of MDZ and its major metabolite after given MDZ by i.v. or p.o. route. So
  I estimate the pre-systemic ERhep and ERgi of MDZ given by p.o. route. Now is it possible to
  estimate how much metabolite is formed by presystemic GI metabolism, presystemic hepatic metabolism
  and systemic hepatic metabolism? If assuming pre systemic and systemic hepatic metabolism are the
  same.
  
  Many thanks
  
  Best,
  Mengyao
  
  

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• On 28 Jul 2013 at 10:03:11, Walt Woltosz sent the message
  

  
  Mengyao Li,
  
  GastroPlus(TM) calculates the formation rate of metabolites in GI, liver, and all other tissues with
  known expression levels of CYPs and other enzymes. You can also track metabolites of metabolites,
  and then their metabolites, etc. to as many levels as you have kinetic parameters to support (Vmax
  and Km).
  
  If they are unknown but you have measured levels of the metabolite(s), you can fit the kinetic
  parameters. It is best to have data at more than one dose to achieve the greatest confidence in the
  fitted parameters.
  
  Walt Woltosz
  Simulations Plus, Inc.
  www.simulations-plus.com
  
  

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• On 29 Jul 2013 at 11:22:06, Rob sent the message
  

  
  Hi Mengyao,
  
  I think you can differentiate  between systemic and pre-systemic metabolism using a
  semi-physiological model for first-pass metabolism, incorporating both IV and PO data, e.g. as
  previously proposed by Levi et al (J Pharmacokinet Pharmacodyn. 2007 Feb;34(1):5-21).
  
  Cheers,
  Rob
  
  

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