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Hello,
I am studying the effects of cigarette smoke exposure on pregnant rats and
mice and I must determine the steady state levels for nicotine
concentrations. There is previous data in our lab but they are taken from
pregnant rats after exposure from day 3 to day 21 of pregnancy. On day 21,
cardiac puncture was done and the plasma sent for GC-MS analysis. Can
I calculate steady state levels from this one data point? How do I use
inhalational kinetics in pharmacokinetic models?
Thanks for your input.
Kimberley Cochrane
Graduate Student
University of Calgary
Imagination is more important than knowledge.
-- Albert Einstein
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Kimberly,
The estimated half-life of nicotine in humans is about
2 hours. It might be a fair assumption that the half-life
in rats is also short. With continued dosing, time to steady
state is 5 half-lives, or around 10 hours in this case.
Mike Leibold, PharmD, RPh
ML11439.-a-.goodnet.com
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Dear Kimberley
Nicotine has a half-life of about 1 hour in rats and mice. If you exposed
the animals for atleast 4-5 hours each day (a typical exposure duration and
which usually does not exceed 6 hours/day) then you may be at steady-state
at the end of the exposure (remember nicotine does not accumulate between
treatment exposure days and hence you cannot claim to be at steady state for
the entire duration of the study). This `daily' steady state value is true
only if you had sampled immediately post exposure. It is difficult to
predict what this steady state value will be because you never know the
exact dose deposited in the lungs and the fraction absorbed. Therefore you
are pretty much in the `hand-waving mode' from the pharmacokinetics
perspective for this route of administration.
We at Battelle have tried to improve on this situation by measuring the
nicotine concentration in the aerosol following generation, determine mass
transfer efficiencies up to the breathing zone of the animal and measure the
minute volume of each animal in real time and continuously. Beyond this
point I resort to a lot of `hand-waving' and hand-wringing' also, albeit I
have gotten good at it.
On the other hand, the dose administered and absorbed from the lungs in
larger animals (dogs and non-human primates) has been better quantified
using gamma scintigraphy and forced respiratory maneuvers.
Hope this was helpful. Good Luck with your research.
Anup Zutshi Ph.D.
Pharmacokinetics and Metabolism
Pharmaceutical Product Development
Battelle Memorial Institute
Tel.No: (614) 424-5997
Fax: (614) 424-3268
E-Mail: zutshi.-at-.battelle.org
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Regarding nicotine pharmacokinetics, the following may be of interest:
A physiologically based pharmacokinetic model for nicotine disposition in
the Sprague-Dawley rat.
Toxicol Appl Pharmacol. 1992 Oct;116(2):177-88.
PMID: 1412462; UI: 93031847
- Rory Conolly
rconolly.at.ciit.org
CIIT
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"Zutshi, Anup (by way of David_Bourne)" wrote:
> Nicotine has a half-life of about 1 hour in rats and mice. If you exposed
> the animals for atleast 4-5 hours each day (a typical exposure duration and
> which usually does not exceed 6 hours/day) then you may be at steady-state
> at the end of the exposure (remember nicotine does not accumulate between
> treatment exposure days and hence you cannot claim to be at steady state for
> the entire duration of the study).
Its not clear to me what Anup has in mind by "steady state".
IMHO steady state describes the situation when the rate in = rate
out. With a constant rate in then one can measure a "steady state"
concentration at some time after a suitable number of half-lives
(lets say 5). But if the dosing is intermittent then we have to
accept that a steady state only occurs at one instant after each dose
-- at the peak concentration. We can however define an average steady
state conc by integrating concs over some interval e.g. the dosing
interval. AUC/dosing interval is the average SS conc. In the case of
a drug with a dosing interval of 5 or more half-lives then the AUC
after the first dose should be the same as the AUC after any number
of similar doses so it is reasonable to say that the first dose AUC
approximates steady state. Thus I think it would be quite reasonable
to "claim to be at steady state for the entire duration of the study".
--
Nick Holford, Divn Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford.aaa.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
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"Nick Holford (by way of David Bourne)" wrote:
>IMHO steady state describes the situation when the rate in = rate
>out. With a constant rate in then one can measure a "steady state"
>concentration at some time after a suitable number of half-lives
>(lets say 5).
Exactly, in this case you do not have a rate in = rate out situation
and hence you do not have a "steady state concentration" that is maintained
between exposures.
>But if the dosing is intermittent then we have to
>accept that a steady state only occurs at one instant after each
dose
>-- at the peak concentration. We can however define an average
steady
>state conc by integrating concs over some interval e.g. the dosing
>interval. AUC/dosing interval is the average SS conc....
Yes you are at steady state at Cmax, but estimating an average steady
state concentration in this case with a dosing interval of 24 hours i.e.
AUC/24 hrs has no pharmacological significance.
Anup Zutshi Ph.D.
Pharmacokinetics and Metabolism
Pharmaceutical Product Development
Battelle Memorial Institute
Tel.No: (614) 424-5997
Fax: (614) 424-3268
E-Mail: zutshi.at.battelle.org
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Anup,
I wrote previously:
> > We can however define an average steady
> > state conc by integrating concs over some interval e.g. the dosing
> > interval. AUC/dosing interval is the average SS conc....
You replied:
> Yes you are at steady state at Cmax, but estimating an average steady
> state concentration in this case with a dosing interval of 24 hours i.e.
> AUC/24 hrs has no pharmacological significance.
Would you please explain why the average steady state concentration
has no pharmacological significance?
--
Nick Holford, Divn Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford.at.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
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Seem like one should be careful in working with "average steady state
concentration" to the extent that it does not actually represent a true
steady state concentration. For example, if the relationship between target
site concentration of the drug and pharmacological or toxicological effect
is nonlinear, then average steady state concentration may convey no useful
information about the overall applied dose-effect relationship. This could
have potentially serious clinical consequences.
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