PharmPK Discussion - Intestinal intrinsic clearance prediction

• On 11 Aug 2011 at 00:57:05, wangjian (wj801126.at.hotmail.com) sent the message
  

  
  Dear All:
  
  I have a question now confusing me. We all know that we can use pooled human liver
  microsomes to perform in vitro assay to calculate Vmax and Km, and then using Vmax/Km we
  can get intrinsic clearance. The predicted in vivo intrinsic clearance can be extroplated
  by multipling MPPGL and liver weight values. If the metabolic reaction we detected was
  mainly mediated by CYP3A4/5, can we use this Vmax and Km data to predict the intestinal
  clearance?
  
  Normally the microsomes vendor will not provide the value of CYP3A4/5 content per mg
  protein, but we know the physiological value of CYP3A4/5 content in liver and intestines,
  so we can get physiological CYP3A4/5 content per protein, is it can be used to
  re-calculate the Vmax from pmol/min/mg protein to pmol/min/pmol CYP3A4?  If so, the
  intestinal microsomes can be got from Vmax/Km*(CYP450 content in intestines).  Is it
  reasonable? Or we must perform another study using intestinal microsomes?
  
  Jian
  

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• On 11 Aug 2011 at 09:00:32, Masoud Jamei (masoud.jamei.at.gmail.com) sent the message
  

  
  Hi Jian
  
  The main issue here is to confirm one pmol of CYP3A does the same job in
  the liver and intestine and this has been shown. So, you are right to
  assume it is possible to extrapolate intestinal clearance from liver
  metabolism data and it has been done successfully for a number of drugs.
  For your information it is also shown that there is a very good degree
  of consistency between clearance values extrapolated from liver and
  intestinal microsomes. Please see the following papers for full details:
  
  Yang J, Tucker GT and Rostami-Hodjegan A (2004) Cytochrome P450 3A
  expression and activity in the human small intestine. Clin Pharmacol
  Ther 76:391.
  
  Yang J, Jamei M, Yeo KR, Tucker GT and Rostami-Hodjegan A (2007)
  Prediction of Intestinal First-Pass Drug Metabolism. Curr Drug Metab
  8:676-684.
  
  Gertz M, Harrison A, Houston JB and Galetin A (2010) Prediction of human
  intestinal first-pass metabolism of 25 CYP3A substrates from in vitro
  clearance and permeability data. Drug Metabolism and Disposition
  38:1147-1158.
  
  Gertz M, Houston JB and Galetin A (2011) Physiologically-based
  pharmacokinetic modeling of intestinal first-pass metabolism of CYP3A
  substrates with high intestinal extraction. Drug Metab Dispos.
  
  Regards Masoud
  
  

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• On 12 Aug 2011 at 01:53:33, wangjian (wj801126.-at-.hotmail.com) sent the message
  

  
  Hi, Masoud:
  
        Thanks for your response. Another my concern is when we use microsomes to get Vmax
        value, the unit will be pmol/min/mg protein, can we directly transform this unit to
        pmol/min/pmol CYP3A4 by the reported value such as 155 pmol/mg protein? When we do
        like this, how to handle the discrepancy among so many products provided by
        different companies and different lots? Can we just assume all the products of
        pooled liver microsomes were uniform and can represent the reality?
  
  Regards,
  Jian
  

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• On 12 Aug 2011 at 13:49:11, Masoud Jamei (masoud.jamei.-at-.gmail.com) sent the message
  

  
  Hi Jian
  
  If microsomes come from single or a few donors then assuming the average
  abundance value couldn't be valid. However if you are using pooled data
  from say 100 donors or more then this assumption might be sensible.
  Alternatively you can characterize microsomes yourself or use the
  supplier values if they have done it.
  
  The average liver CYPs abundances can be found in the following article:
  
  Rowland-Yeo K, Rostami-Hodjegan A and Tucker GT (2003) Abundance of
  cytochrome P450 in human liver: a meta-analysis. Br. J. Clin. Pharmacol
  57:687-688.
  
  Regards
  Masoud
  
  

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