PharmPK Discussion - PK Puzzle

• On 25 Nov 2007 at 12:59:06, "GHOBRIAL,OLIVER G" (oliver1.at.ufl.edu) sent the message
  

  
  This one is for all the PK gurus out there.  OK, here it is.
  I dosed this drug IV, two shots, one week apart and collected blood in
  both experiments.
  
  First experiment: (time, conc ug/ml)
  (5min, 25)
  (10min, 4)
  (15min,12)
  (30min, 6)
  (1hr,15)
  (2hr,1)
  (4hr,1)
  
  So as you would imagine the concentrations zigzag for about 4 hours
  and then drops below the LLOQ.
  When I repeated the experiment, using the same animal, same dose, I
  got the same zigzag profile, but the concentrations are much lower,
  and nothing is detectable after 30min.
  
  First issue: zigzaging concentration profile after an IV bolus.  I
  have no idea why that is?
  Second issue: diminished concentrations after administration of the
  same dose.  I'm thinking may be induction or upregulation of a
  biotransformation enzyme?
  
  Your thoughts are greatly appreciated
  Oliver
  
  

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• On 25 Nov 2007 at 13:57:40, "Peter Bonate" (peter.bonate.-a-.gmail.com) sent the message
  

  
  The following message was posted to: PharmPK
  
  The first thing I would look at is the assay.  Are your assay results
  valid?  I would then look at stabilty.  Is there something going on
  after you collect the samples?  Possible degradation that might vary
  from one sample to the next.  Can there be redistribution from RBCs to
  whole blood?  I would want to look at all other exogenous reasons
  before I go start looking for physiologic reasons.  The time course of
  your study seems too short to consider upregulation.
  
  pete bonate
  
  --
  Peter Bonate, PhD, FCP
  
  

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• On 26 Nov 2007 at 09:08:28, "Nadeem Irfan Bukhari" (nadeemirfan_bukhari.aaa.imu.edu.my) sent the message
  

  
  The following message was posted to: PharmPK
  
  Dear Oliver
  Zigzaging in drug profile may be due to distribution and
  re-distribution phenomenon or chances of eratic bioavailability. For
  second issue, we also found a drug with low plasma concentration in a
  cross over study. May be it is worth to mention the vehicle of the
  drug.
  Thanks
  
  Nadeem Irfan Bukhari
  
  

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• On 25 Nov 2007 at 21:40:02, "GHOBRIAL,OLIVER G" (oliver1.aaa.ufl.edu) sent the message
  

  
  The following message was posted to: PharmPK
  
  Dear Nadeem,
  the vehicle is saline.  What do you mean by distribution and re-
  distribution phenomenon?
  Many thanks
  Oliver
  
  --
  
  Hi Pete,
  I validated the assay and all the QCs have passed with accuracy above
  95%. I tested the analyte stability in plasma and no loss is evident
  for up to 4 hours (I didn't test further than that).  Furthermore, all
  samples have been spiked with an ISTD before extraction.  The ISTD is
  an identical molecule (almost) and there is very little fluctuation
  from one sample to another (+-10%). I would be surprised if anything
  is happening post collection that causes this zigzaging.
  Regarding the redistribution from RBCs to whole blood, can you
  elaborate on that, any references would be greatly appreciated.
  Many thanks
  Oliver
  
  

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• On 26 Nov 2007 at 07:55:32, aganza.-at-.faes.es sent the message
  

  
  We have had quite a similar problem with a new drug intensively
  distributed to RBC.
  Plasma concentration seemed to be extremly variable... but after a
  closer look, it was related to haemolysis during sample extraction.
  (the higher the haemolysis the higher the concentration).
  Hope this helps.
  Regards.
  
  

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• On 26 Nov 2007 at 11:11:06, "Noha Salama" (nohasalama.-at-.gmail.com) sent the message
  

  
  Hi Olivier
  a classic example of redistribution between RBCs and plasma is
  cyclosporin ( CSA).  you can do a pubmed search to see the changes in
  CSA concentrations and why CSA is usually measured in blood versus
  plasma because of this high variability. Many factors affect the
  redistribution including the sample temperature, the standing time
  before centrifugation, etc...
  hope this helps
  Noha
  
  

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• On 26 Nov 2007 at 16:38:26, "Nadeem Irfan Bukhari" (nadeemirfan_bukhari.-a-.imu.edu.my) sent the message
  

  
  The following message was posted to: PharmPK
  
  Dear Oliver
  
  One of the reasons for zigzag profile may be due to drug distribution
  to some tissues from where it is again distributed to blood and so on.
  Howerver, there are other reasons as well. Tissue distribution study
  may give some information. However, Peter Bonate has rightly stated to
  check for the exogenous reason before assessing the physiologic
  reasons.
  
  Vehicle was asked becasue, in our study, we administered drug as
  nanoparticles and found drug with multipeaks in first session and in
  second session, very low drug concentrations in all rats. Being normal
  saline, the vehhicle does not seems to influence such profile.
  
  Thanks and regards.
  
  

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• On 13 Dec 2007 at 14:12:52, alain.munafo.-at-.merckserono.net sent the message
  

  
  Hi,
  
  What about the solubility, can the drug precipitate after it is
  injected?
  Alain
  
  

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