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The following message was posted to: PharmPK
Dear Colleagues,
A NCE shows a bi-exponential profile with a small rise
in drug level shortly after the beginning of the
second phase, which may indicate the presence of
enterohepatic circulation. However, this was
predominantly observed following the first dose
(cycle) and somewhat disappeared following subsequent
doses (cycles). Any explanations would be
appreciated.
Rostam
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The following message was posted to: PharmPK
Dear Rostam
Have you considered induction of metabolism? Does the NCE have
faster elimination and/or clearance on repeat admn?
With regards
Dr. Prashant
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The following message was posted to: PharmPK
Dear Rostam,
You could consider:
- change in absorption processes as a consequence of repeated dosing.
The
double peak could be related to a second absorption window (see [1] for
some
background/models), delayed gastric emptying, pH related issues (did you
administer a solution?), etc. The subsequent disappearance after
repeated
dosing could than be due to any change in these processes - inhibition,
induction, any accomodation/ homeostatis type of change - Could the
compound
have an effect on typical GI parameters?
- changes in feeding regime
- some statistical issue, like variability in the assay. If you know
the SD
of the assay at that concentration, your rise should be twice that value
(rule of thumb) if you want to discard assay variability. Did you see
the
phenomenon in multiple individuals?
- also statistical: issues with intermittent (matrix) sampling in
rodents,
you could see a double peak that is due to interindividual var.
A question for you: did you see a delayed peak after iv-dosing? That
would
be necessary to conclude circulation, entero-hepatic or otherwise.
Best regards,
Jeroen
[1] Zhou, H. (2003). Pharmacokinetic strategies in deciphering atypical
drug
absorption profiles. J.Clin.Pharmacol. 43, 211-227.
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)