PharmPK Discussion - Changes in metabolism with slow release formulations

• On 20 Mar 2014 at 11:51:57, Mary M Sherman (marymsherman.-a-.VERIZON.NET) sent the message
  

  
  Has anyone observed a shift in rate or extent of metabolite formation/excretion when changing from
  immediate release to slow release formulation?
  
  MMS
  
  

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• On 20 Mar 2014 at 18:52:09, Walt Woltosz (walt.aaa.simulations-plus.com) sent the message
  

  
  Mary,
  
  You asked, "Has anyone observed a shift in rate or extent of metabolite formation/excretion when
  changing from immediate release to slow release formulation?"
  
  This could easily happen, especially for a 3A4 substrate. A slower release could allow drug to be
  release after a substantial part of the dose had transited past the regions of high 3A4 expression
  in the proximal small intestine. This is just one example, but any drug that is either metabolized
  in the gut wall or is a substrate for gut wall transporters could have it’s absorption into the
  enterocytes and it’s first-pass metabolism in the gut affected by where the drug is released.
  
  Best regards,
  
  Walt
  
  Walt Woltosz
  Chairman and CEO
  Simulations Plus, Inc. (NASDAQ: SLP)
  42505 10th Street West
  Lancaster, CA 93534
  
  

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• On 21 Mar 2014 at 09:06:35, Andres Olivares morales (andres.olivaresmorales.aaa.manchester.ac.uk) sent the message
  

  
  Hi:
  
  There are a few examples on the literature for this, especially for intestinal first pass metabolism
  of CYP3A substrates, where the CR formulation can show even higher relative bioavailability than the
  IR product. However, the observables changes( Cpt profile and AUC for instance) might be dependent
  on the absorption characteristics of your compound, as the absorption potential seems to be reduced
  in the distal regions of the GI tract.
  
  Some references:
  
  Gupta, S. K.; Sathyan, G.  Pharmacokinetics of an oral once-a-day controlled-release oxybutynin
  formulation compared with immediate-release oxybutynin. J. Clin. Pharmacol. 1999, 39, (3), 289-96.
  Sakr, A.; Andheria, M.  Pharmacokinetics of buspirone extended-release tablets: a single-dose study.
  J. Clin. Pharmacol. 2001, 41, (7), 783-9.
  
  We’re currently investigating on this particular topic ( CR vs metabolism)
  
  Best wishes,
  
  Andrés
  
  Andrés Olivares-Morales, Pharm.D.
  PhD Candidate
  Centre for Applied Pharmacokinetic Research
  Manchester Pharmacy School
  The University of Manchester
  
  

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• On 21 Mar 2014 at 09:07:39, Angusmdmclean.at.aol.com sent the message
  

  
  Mary:  Check out oxybutynin (see below link).   The bioavailability of oxybutynin relative to IR is
  increased when delivered to the colon (see below).  Walt is correct.
  
  http://www.ncbi.nlm.nih.gov/pubmed/10073329
  
  Hope this helps,
  
  Angus McLean
  
  

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• On 22 Mar 2014 at 14:21:05, Uwe Fuhr (uwe.fuhr.-a-.uk-koeln.de) sent the message
  

  
  See also for respective properties of ipsapirone:
  
  http://www.ncbi.nlm.nih.gov/pubmed/7946942
  
  Best regards, Uwe
  
  

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Copyright 1995-2014 David W. A. Bourne (david@boomer.org)