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I am looking at very basic PK parameters of a water soluble compound
administered IV to nude mice. My cMax value obtained 5 minutes after IV
bolus injection is only 5-10% of the administered dose. Concentrations
at later sampling times continue to decline. I don't believe I am
having any problems with precipitation because this compound is very
water soluble (It is a salt). In vitro it appears stable in plasma at
37 degrees for at least an hour. What possible explanations are there
for this very low value? Should I try to sample at an earlier time
point?
Thanks,
Noelle
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Dear Noelle,
did you consider the compartment of Red cells ?
You can have a Kaf for these cells higher than in plasma.
Try to quantify your drug after a compleate hemolisys.
Best regards and let me know
fabio
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dear noelle,
there could be possibility of lung metabolism.
Also try to analyse as whole blood instead of plasma
drug concentration.
regards
sivakumar
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Dear Noelle williams,
Was 5min was the first time point? ususally after IV dosing it is
always better to take a 0min to 1min time points, you will get more or
less the accurate C0, than extrapolating from 5 min time point. If the
molecule has rapid distribution you may miss that phase.
Less Cmax may also be due to rapid distribution. What is the logp or
logD or that particular molecule?
Regards,
Suresh.B.L
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Dear Suresh,
You wrote:
"Was 5min was the first time point? ususally after IV dosing it is
always better to take a 0min to 1min time points, you will get more or
less the accurate C0, than extrapolating from 5 min time point. If the
molecule has rapid distribution you may miss that phase."
I agree that a first time point at 5 min may result in 'missing' a rapid
distribution phase. But I have two comments:
1) Samples taken within 1 min (in man and large animals: 2 min) may give
false results, since the plasma concentration does not decline
exponentially, but will oscillate due to dilution of the bolus dose in
the
vascular system. This is the very reason why samples within 1 or 2 min
are
not used in most pharmacokinetic studies. Of course the time points of
1 and
2 min are somewhat arbitrary, and depend on circulating volume, cardiac
output, duration of administration, etcetera.
2) It is a matter of debate whether or not we are really interested in a
precise determination of a (very) rapid distribution phase.
Theoretically,
the initial volume of distribution should be similar to the circulating
volume; any value found for the initial volume larger than this implies
some
initial distribution. If this distribution is 'very rapid', we will
never be
able to characterize the rate constants for this process, but it also
would
not be really relevant, since the drug distributes 'immediately' over
the
(large) initial volume. Of course, the definition of 'very rapid' is
arbitrary, but it is clear that 'missing a rapid distribution phase' is
not
always relevant.
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.at.farm.rug.nl
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I have a similar situation. With our compound the RBC binding is only
~20% and the other characteristics are similar to those you describe for
your molecule. Can anyone comment as to whether this is an issue
related to nude mice compared to normally immunocompetent mice? One
suggestion, but I don't have references, was that the mouse tail vein is
somewhat "porous" and some compounds leak into the surrounding tissues
thus lowering the expected Cmax.
Garry
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Dear Noelle,
You wrote:
" My cMax value obtained 5 minutes after IV bolus injection is only
5-10% of the administered dose."
I assume this means that your estimate of the volume of distribution
(Vd) is a large value, since Cmax (concentration) and dose (amount) are
not directly comparable. Could you provide the values for the Vd and
clearance (CL) that you have estimated?
Toufigh Gordi
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Vd = 1307.7 ml
Cl = 1.32 ml/min
nude mouse average weight 21 g
Estimated blood volume of mouse: 1.575 ml (from Tse and Jaffe,
Preclinical Drug Disposition, 1991 - Appendix IV)
*my fractional estimate of administered dose (Conc at 5 min X 1.575 ml)
is really too high - it's more like 4-5% although as you point out
below this is not really a fair comparison
Conc. at 5 minutes: 5773 ng/ml
Dose: 210,000 ng
Noelle
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Dear Noelle,
You wrote " My cMax value obtained 5 minutes after IV bolus injection is
only 5-10% of the administered dose."
I am thinking apart from the things which taufigh suggested, you need to
highlight tissue levels of drug at initial time points ( Plasma to
tissue
ratio particularly in lung and liver) This could better explain whether
Vd
is contributing towards lower Cmax.
In addition to this metabolic identification in plasma sample at initial
time point would be helpful. Have you checked stability of your drug in
whole blood at 37 C.
Vinod Patil & Amol Raje
DMPK Lab
Wockhardt Research Centre
India.
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Dear Noelle,
As you can see, your estimation of Vd (~1307 mL) is much higher than
the actual blood volume of the mouse (~1.6 mL). This suggests that you
have a high partition of your compound to some tissue, which could be
true. I guess the strange thing is that it happens so fast with very
low concentrations already after 5 minutes. Do you have any data at
earlier and later time-points, let's say 2-3 minutes and 7-10 minutes
post-dose? If you have done any modeling (or looking at the
concentration vs. time graphs), do you see a bi- or multi-compartment
profile of the compound?
I am excluding the possibility of errors in dosing, as I am sure you
already have checked that out.
Toufigh Gordi
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