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We currently have the same problem with our mass balance experiments:
the recovery is close to 95% after a single oral dose while it is
around 75% after a single intravenous.
Any idea of what can be happening?
L. Monlauzeur
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If your drug is 14C labeled, and you are not collecting exhaled air, you
could be losing a portion of your label through CO2 production following
intravenous administration. If your drug has poor oral bioavailability,
the loss through this route would be much less after oral
administration.
Peter Rix
Ligand Pharmaceuticals, Inc.
San Diego, CA
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Dear Laure,
some thoughts about potential reasons for your discrepancies,
unfortunately
without knowing the exact details of your study design. The good
recovery
after oral dosing might be a reflection of poor oral absorption. An
experiment in bile-duct cannulated animals and an identification of the
nature of radioactivity in the feces of the excretion balance experiment
might give you a hint. Concerning the iv data, the simplest
explanation is
an insufficiently long sampling period.
Best regards
Alex
Alexander Treiber, PhD
Head, Preclinical Pharmacokinetics and Metabolism
Actelion Pharmaceuticals Ltd / Gewerbestrasse 16 / CH - 4123 Allschwil /
Switzerland /
phone +41 61 565 6592 / fax +41 61 565 8903 /
alexander.treiber.-at-.actelion.com / www.actelion.com
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I am assuming that this was a radiolabeled study. When calculating
recovery did you take account of radioactivity remaining in the
carcass? Even if the half-life is short there can be residual
compound, either because of a slow-equilibriating compartment or due
to covalent binding. I don't know what your plasma concentration
time profiles looked like but if the intravenous dose gave you a much
higher Cmax than the oral dose this could have resulted in a switch
in the route of metabolism. For example, a low concentration of
compound after oral dosing could be metabolised to an electrophile
which could be trapped efficiently by glutathione (and then excreted
and recovered). A high spike in the concentration, such as after
intravenous dosing, could result in the generation of larger amounts
of electrophile which overwhelm detoxication and bind covalently to
tissue proteins and are thus not recovered in excreta.
As another person mentioned, metabolic loss of 14C as 14CO2 or 3H as
3H2O, are also possibilities. The CO2 would be lost in expired air
while the tritiated water would likely have a much longer half-life
than the parent and would remain in the carcass.
I hope that this helps.
Bernard
Bernard Murray, Ph.D.
Senior Research Scientist, Drug Metabolism
Gilead Sciences
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Thanks Peter,
Our drug is 14C labeled but we do collect the exhaled air (in a
barium hydroxide solution) after IV injection and no radioactivity
was detected.
To be more precise about what we do: we collect and count the
radioactivity in the urine, feces, expired air, cage wash and carcass
(digested in 500 mL of NaOH 5N during one week at 50*C and then mixed
with an Ultra Turax).
Our two hypothesis:
1) we have a problem to determine the administered dose with the IV
solution which is 5 times more concentrated in radioactivity than the
oral one. We realised several test and this do not seem to be the case.
2) there is still radioactivity in the carcass and our procedure to
homogenize it is not OK. We will test this by removing some organs
and the tail and digest separately the organs, the tail and the carcass.
Any other idea?
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Dear Laure:
Other colleagues provided several potential
explanations. The only thing that I can add is the
dosing accuracy. Have you checked these data and they
are ok? Particularly for iv injection, if you miss
the blood vessel and create a depot due to drug
precipitation then it may take much longer to recover
all the administered dose in the excreta. If you
measured radioactivity in the carcass including tail
then you are ok. You noted that without knowing the
details of your experimental I made several
assumptions regarding to the design of your study. It
would be nice if you can provide more details and this
discussion would be more educational and useful in
problem solving like this in the future.
Rostam
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Dear Laure ,
There is often a problem during application of an intravenous dose
due to
loss of material in the syringe or reservoir over time. Do you see a
drift
from animal to animal? May be the syringes are too big for
application of a
very small volume. If the formulation is not suitable or injected too
quickly the compound may precipate after injection. You will find it
in the
carcass and you can see the problem in the conc/time profile of your
compound.
Kind regards
Thomas
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I am looking for a good candidate compound to use as a model compound
and teach procedures in conducting a mass balance study in rats, dogs
and monkeys.
Can someone suggest a compound that is commercially available as a
C-14 labeled compound with high purity and has well characterized and
published data on excretion and radioactivity recovery results in
rats, dogs and monkeys. Thanks for any assistance.
Karsten A. Holm, Ph.D.
MPI Research
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Aspirin.....
Michael Chansler
Vice President Business Development and Sales
Accium BioSciences
550 17th Avenue, Suite 550
Seattle, WA 98122
Tel: (206) 281-3915
Fax: (206) 281-5916
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