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Dear All,
Has anybody seen a Cmax after a 15 min infusion happening after the end
of the infusion?
If yes, what would be an explanation for that? Could it be possible to
observe such a phenomenom after single dose but not after multiple dose?
Thanks in advance for your input/comment
Best regards
Nathalie Toublanc
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One way for this to happen is with a very insoluble compound. When it
first hits the blood the local concentration is very high and it
precipitates out in the veins and then slowly redissolves. The highest
concentrations at the early timepoints are in the lungs, which is where
microemboli (which is effectively what you have at that point) are
filtered.
Dale Sharp
Purdue Pharma
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Dale,
This is very intersting! Do you have experimental evidence of this
phenomenon, either from your own lab, or perhaps you've seen this
published
somewhere?
With thanks,
Jackie
Jacqueline Gibbons, Ph.D.
Piedmont, California
gibbonsj.-a-.pacbell.net
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Hi Nathalie,
one thing that springs to mind on this early morning is to check (I'm
sure
you've done it!) that what you are measuring, is really the drug itself
and
NOT drug + coeluting material?
Is-it linear kinetic or is there inhibition/induction/accumulation?
Kind regards,
Pascal
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Jackie,
Yes, the compound in question was highly lipophilic, and we were doing
a radiolabeled tissue distribution study in rats using a short IV
infusion, just as you were. The reason we were doing an infusion
rather than a bolus was due to the insolubility of the compound, which
meant that the volume of the IV vehicle was too great to allow a bolus.
We had euthanasia times at 5 and 15 minutes after the end of the
infusion. That rats showed some immediate and short lived clinical
signs of distress, mostly elevated breathing rate. The plasma
radioactivity Cmax was at 15 minutes postinfusion rather than 5. There
were very large amounts of radioactivity in the lungs at 5 min
postinfusion, which diminished very rapidly. In my experience, it is
very rare for the lungs to have the highest amounts of radioactivity in
a TD study. At 15 minutes and other times the liver had the highest
concentration. I interpreted that data as a result of precipitation.
Dale
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Dear Dale,
We did think about that, the problem is that the drug is highly
soluble, so this hypothesis is unlikely.
Regards
Nathalie
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Is there a possibility of extravasation of the dose during the infusion?
Shelly Dunnington R.Ph., Ph.D.
DunningtonShelly.-at-.praintl.com
913-577-2767
16400 College Blvd.
Lenexa, KS 66219
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Is there a possibility of extravasation of the dose during the infusion?
Shelly Dunnington R.Ph., Ph.D.
DunningtonShelly.aaa.praintl.com
913-577-2767
16400 College Blvd.
Lenexa, KS 66219
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Dear Shelly
your question is bit incomplete. You said dose and not the drug.
if you could please clarify underlying problem it would be
appropriate to make a comment. are you falling short very
significantly in mass balance study?
with regards
Prashant Bodhe
Ph.D.
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Dr. Bodhe,
Sorry for the confusion, my question is actually in response to the
previous
issue about a delayed (I think) Cmax well after an infusion has ended.
Leakage of the dose outside of the vein may have some delayed
absorption,
more like an IM or IP dose.
Shelly Dunnington R.Ph., Ph.D.
DunningtonShelly.-at-.praintl.com
913-577-2767
16400 College Blvd.
Lenexa, KS 66219
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Dear Shelly
If I recollect reading your mails then the compound under
investigation is highly soluble. Just check whether it is highly
or moderately permeable. In that case enterohepatic recycling, as
suggested by someone (sorry i do not recollect name), is close to
what I think is happening - distribution and redistribution. Later
may be happening because concentration flux in the circulation
stops growing once infusion stops.
I hope this provides at least partial explanation.
with regards
Prashant
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Dear Shelly,
Have you checked that there are no metabolites interfering with the
assay?
Another possibility might be that you are seeing metabolites that
convert back to the parent compound (it can happen, especially when
using LC-MS-MS methods).
In both cases you will see an increase in the plasma concentration
sometime after the end of the infusion when enough of the
interfering/converting metabolite has formed.
One suggestion might be to run a classical stability trial with real
samples (collected after the iv dosing of the subjects). If you see
that the concentration of the parent assayed at time zero, increases
during storage, you will have a further indication that there are
metabolites converting back to the parent.
Stefano Persiani, PhD
Director, Drug Metabolism and Pharmacokinetics
Rotta Research Laboratorium SpA
Via Valosa di Sopra, 7-9
20052 Monza (MI)
ITALY
Tel. ++39-039-7390-318
Fax. ++39-039-7390-371
e-mail: Stefano.Persiani.at.rotta.com
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