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The following message was posted to: PharmPK
Dear pharmcokinetic colleagues,
Recently I had analyzed a novel drug PK in rat model and have
accumulated a number of PK parameters based on my preliminary studies
in rats, using noncompartmental analysis. The drug shows a very high
oral bioavailability in the dose that was administered (close to 1),
we were however, unable to recover more than two percent of this drug
in its unchanged form in urine. The drug had a low total body
clearance and a relatively low Vd. We know from our in vitro studies
that this drug has a fairly high plasma albumin binding (75%)and is
very lipophilic. I did try to estimate both sulfate conjugate and
glucuronides in the urine of the rats (using enzymatic hydrolysis
methods) and an estimated 8-12% of the drug was found to be in form
of these two conjugates in the urine. This compound is very stable in
vitro and doesn't show any metabolism when incubated with rat liver
microsomes or in plasma. It does carry an iodine, which may come off
of it in vivo, but we do not have any reference with regards to its
metabolism or PK behaviour and we have not identified the possible
ther metabolites in the urine. This compound may have the potential
to be incorporated into DNA of cells, but if so one would have
expected a high Vd I would imagine, unless I am wrong or missing
something here.
Can anyone please help me here with any suggestions as to what may be
going on with this compound? I summerize some of the characteristics
here:
Very stable in the vivo
Very high oral bioavailability
high Log P
High protein binding
Low-medium total body clearance and Vd
*Very little(2%) recovered UNCHANGED in the urine that was
accumulated for 24 hours post dosing
8-12% sulfate and glucuronide conjugates estimated in the urine
Thank you very much for any suggestion as to where this compound may be going.
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The following message was posted to: PharmPK
Hi:
Some sulfate conjugates are not well hydrolysed by sulfatases e.g. steroid
sulfate conjugates. May be you need to try acid hyrolysis and see how much
you can recover in this fraction.
Regards,
Dr. Ibrahim Wasfi
Forensic Science Laboratory,
P O Box 253, Abu Dhabi,
UAE
Fax 00971 2 4463470
Tel 00971 2 4092522
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The following message was posted to: PharmPK
Look into the bile of your rats, or if this is not feasible into the feces.
I bet you will find the unchanged drug there. By the way: I do not consider
a plasma protein binding of 75 % as high as at any given time 25% of the
drug is unbound. 99 % and more is regarded as high binding. If the drug is
distributed into cells additional binding to DNA won=B4t increase the volume
of distribution.
Regards,
Bernhard
Bernhard J. Ladstetter, Ph.D.
Head of Metabolism, Bioanalytics & Radiolabelling
Institute of Pharmacokinetics and Metabolism
Merck KGaA
Germany
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)