Back to the Top
Dear all,
I was wondering if anybody in the group could kindly give me some
hints to explain a compound's PK profiles in dose proportionality
studies.
1. With dose increasing proportionally, plasma exposure in rats after
single oral administration increased less than the dose proportion.
In the high dose range, second peak was observed after 24 or 48 hour
of administration and its concentration is higher than the first peak's.
My question was: 1. Could the presence of second peak be due to the
delayed absorption or the later release from tissue as this compound
was highly protein bound (90%)? And how dose it happen only in high
dose range?
Thank you in advance.
--
Hong Lu
Back to the Top
capacity of transport/storage/degradation
Back to the Top
Lu,
It's hard to give a clear answer without much detail...
-Which analytical detection method are you using (LC-MS/MS or any
other)?
-Does your molecule have a chiral center? Possibly a chiral inversion.
-Do you know the MW of second peak and the fragment information from
their product ion scans?
-delayed absorption of parent should not give a second peak. You
should see an increase or decrease in parent but not a second peak.
-pH of the samples in question different from rest of the samples?
Certainly a change in pH can affect the peak ratio as well.
Regards,
Anila
Back to the Top
The following message was posted to: PharmPK
Um...I have a not very polite suggestion that...in my experience rats
will
eat their feces.
If , for example, you had the test subject rats in a cage where the
feces
was allowed to collect, then you may see a second peak because the
rats have
in fact been re-dosed by eating the excreted unchanged drug that left
the
body thru the colon.
Anyway, just a thought. Good luck!
Back to the Top
The following message was posted to: PharmPK
Dear Lu,
It looks on the face of it that at higher doses you're inducing the
formation of a phase II conjugate which undergoes enterohepatic
recirculation (subsequent hydrolysis back to the aglycone you are
measuring and GI re-absorption). This is not unusual as clearance by
a solely P450 route can be (and frequently is in research studies)
saturated and phase II biotransformations generally are difficult to
saturate and so can be used by the body as a "back-up" clearance
mechanism. If you are using MS/MS to measure this compound, there
*may* be some evidence of this in your compounds MRM chromatogram
e.g. increasing peak(s) either before or after your main analyte
(some conjugates can be less polar than your analyte). This is caused
by insource fragmentation back to the aglycone and subsequent
detection as such.
I think more work on meta ID on your in vivo samples is in order to
ID the relevant conjugate(s) e.g. glucuronidation, acetylation,
glutathionation etc. etc. There are many, many protocols available to
help you with this.
Regards,
Iain
Dr Iain A. Stuart
Preclinical Development
Cyclacel Pharmaceuticals, Inc.
Dundee Technopole
James Lindsay Place
Dundee
DD1 5JJ, UK
Back to the Top
The following message was posted to: PharmPK
Hello
Do you know whether or not your drug has glucuronide metabolites as
the minor
route of elimination? The secondary peak can be resulted from
entrohepaatic
recirculation of glucuronide metabolite. It may be possible that as
the dose
increases the glucuronide route becomes more prominent hence you see the
secondary peak.
Hope it helps.
Fatemeh
Back to the Top
The following message was posted to: PharmPK
Dear Lu,
Is your drug not a substrate of P-glycoprotein.
P-glycoprotein will extract the drug into bile and then reabsorption.
By higher doses due to synergism between metabolism and efflux, if
metabolism is saturated more efflux may occur and then more
reabsorption.
Dr. Sima Sadrai
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "Second peak with increasing oral dose" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)