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Dear readers,
I´m working with compounds intended for topical administration that
have secondary effects related to their systemic exposure. To select
candidates we carried out intravenous PK studies in rat and we applied
non-compartmental analysis to estimate the PK parameters (clearance,
volume of distribution and terminal half-life).
First, we started to select those compounds with the highest total
plasma clearance to ensure a low systemic exposure. However, in some
cases we have found that high values of clearance (> 3 l/h/kg) were
associated with high volume of distribution and short half-life.
Taking into account that we are looking for compounds with low
systemic exposure, are we following the right criteria by selecting
compounds based upon their clearance values? Do we have to take into
account the volume of distribution besides clearance and in which
sense? Any suggestions will be welcome
Thanks
Raquel
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The following message was posted to: PharmPK
Dear Raquel,
What about the applicability of Pharmacoscintiography( Radiotracers)
studies in such cases.
I think a Gamma Scintigraphic evaluation can provide you a valuable
estimate of the sytemic exposure with a fair idea about the site of
distribution also.Although you may find it a bit expensive and
dexterious one( the tagging of compound with radiotracers like
Technitium etc.) but this is a rapid and reliable screen tool for both
qualitative and quantitative estimation of the degree of sytemic
exposure after oral/nasal/pulmonary etc.administration of
investigation drugs and drug delivery systems.
I would like to have feedback of group on this application in drug
discovery.
Kind regards,
Pradeep Bhadauria
RANBAXY RESEARCH LABORATORIES
INDIA.
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Dear Raquel,
Clearance and volume are often (but do not have to be) highly
correlated within compound series'. More hydrophobic drugs tend to
partition better into tissues (hence high Vd) but that includes the
liver (hence higher CL as long as there is sufficient intrinsic CL).
Plasma protein binding (fu) is also part of the process and correlates
with hydrophobicity. The problem is that to gain skin penetration, you
will need a relatively hydrophobic compound. Catch 22. Therefore for
safety you will need a high CL as you state, but the little that does
permeate far enough to reach the blood will be taken round to other
tissues and partition there, with the potential to cause toxicity if
there are adverse mechanisms in that tissue.
As always, a delicate balance is required.
If you want to see the dependence of tissue partition on hydrophobicity
you could try the PBPK modelling technique with unbound partition
coefficients (Kpu) correlated with physicochemical properties, such as
in Poulain & Theil (2002 J. Pharm. Sci 91, 2 articles), Ballard et al
(2003 Pharm Res 20, 864) or incorporated in the PK-Sim software
(http://www.pk-sim.com). However, a specific skin compartment would
have to be added to take the topical dose, which will need an estimate
of the permeation rate to connect everything up.
Best regards, Phil.
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The following message was posted to: PharmPK
Dear Raquel,
Here comes some thoughts on you mail. if I understand correctly, you
are trying to find a candidate compound for topical administration. And
you want to get high local but low systemic exposure. Systemic exposure
for any compound is a balance between how much that gets into the
system (i.e. dose and the fraction of it that actually reaches the
circulation if given other route than iv) and how much that is cleared
from the system (i.e. clearance of the compound). Volume of
distribution will affect the maximum concentrations reached but will
not change the systemic exposure, measured as AUC. Thus, if the
unwanted effects are related to maximum concentrations rather than AUC,
it might be a good idea to look at compounds with high Vd. The effect
of volume of distribution was recently discussed on this server and you
may find it in the archive.
Let's not forget the other important parameter, the bioavailability of
your compound after tropical administration. Beside looking at CL, you
may also try to find compounds with less ability of penetrating the
skin.
Toufigh Gordi
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)