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Dear All,
We are dealing with a series of new chemical entities(NCE) that have
very high total clearance in rats after an intravenous administration,
usually much higher than blood flow to the liver. The compounds in
general are liphophilic in nature with log P between 2 and 3. Many of
the compounds in the series have pH dependent solubility and are
administered around pH 5.5, where they are soluble with 20%
Hydroxy-propyl Beta cyclodextrin, allowing us to dose at 5 mg/Kg. In
order to determine the reasons for this high clearance we have looked at
different possibilities. We found high accumulation in liver, kidneys
and lung comparable to a reference compound (structurally related) with
much lower clearance at 5min samples, indicating no significance
difference at the initial distribution phase between a very high and
very low clearance drugs. We investigated if these compounds were
substrate for PGP utilizing Caco-2 monolayers. Results indicated that
they were not. Some compounds have high protein binding and some are
less but in both cases the clearance was still higher than the blood
flow to the liver. We have also explored the metabolism some of these
compounds in vitro using microsomes and hepatocytes. One particular
compound has a total clearance of 3.0 L/hr/kg which is stable in the
microsomes for 30 min incubation, 87% remaining at 3hr in hepatocytes
and 32% remaining at 9hr.
We believe obviously that there may be several mechanisms responsible
for this high clearance. I would appreciate comments on the the possible
reasons that might be further explored for this high clearance or share
experience that you might have on a similar situation.
Thanks
Jehangir
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The following message was posted to: PharmPK
One possibility is the involvement of uptake transporters like OATPs.
Regards,
Bernhard J. Ladstetter, Ph.D.
Institute of Pharmacokinetics and Metabolism
Merck KGaA
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The following message was posted to: PharmPK
Dear Jehangir,
Is it your total blood clerance or your total plasma clearance that is much
higher
than liver perfusion?.
If you are estimating the clearance using plasma data, you should determine
the
blood to plasma ratio as the ratio between blood concentration (Cb) and
plasma
concentration (Cp). If Cb >> Cp, it might explain your findings.
You suggested drug accumulation in several tissues as a possibility.
However drug accumulation relates with drug distribution, and not with
drug elimination since both processes are independent. Perhaps, the high
tissue
accumulation prevents, under your study design, a proper estimation of the
pharmacokinetic parameters. You gave the drug intravenously, what about a
first-pass effect in the lung?,
Hope this helps,
best,
I=F1aki
I=F1aki F. Troc=F3niz Ph. D
=46armacia y Tecnolog=EDa Farmac=E9utica
=46acultad de Farmacia
Universidad de Navarra
Pamplona 31080
Spain
Tph. +34 948 42 56 00 ext 6507
=46ax. +34 948 42 56 49
e-mail. itroconiz.-at-.unav.es
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