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The following message was posted to: PharmPK
Dear All,
Is there any generalized correlation for Dose and clearance ?
Or Can Clearance be calculated for varying doses (amount of drug in
the body) (Either Oral or IV) ?
Thanks & Regards,
Neha Bhandari
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Neha,
You asked:
> Is there any generalized correlation for Dose and clearance ?
The first fundamental relation in pharmacokinetics is:
Rate Out = Clearance x Concentration
At steady state this means:
Rate In = Clearance x Concentration
If you replace the Rate In by the maintenance dose rate i.e. the "dose":
Maintenance Dose Rate = Clearance x Concentration
This shows the answer to your first question. The "correlation"
between dose and clearance is 100%. Indeed you can think of clearance
as the factor that "correlates" dose and concentration.
It also shows the answer to your second question. Clearance can always
be calculated from the dose rate and the steady state concentration.
There are very well known methods for calculating clearance from non-
steady state concentrations described in pharmacokinetic textbooks. In
nearly all cases clearance is a constant for a particular drug so you
only need to study concentrations after one dose to calculate the
clearance (see below for more details).
With regard to your second question:
> Or Can Clearance be calculated for varying doses (amount of drug in
the body) (Either Oral or IV) ?
The amount in the body is only equal to the dose at the instant the
dose is given -- after that the amount will decrease (due to
elimination by a clearance process).
The second fundamental relation in pharmacokinetics is:
Amount in Body = Volume of Distribution x Concentration
See these links for more details about the basic ideas about clearance
and volume of distribution and some of the more complicated issues
such as capacity limited elimination when clearance will change
depending on the dose:
http://www.fmhs.auckland.ac.nz/faculty/teaching/mbchb209/_docs/clearance_ppt.pdf
http://www.fmhs.auckland.ac.nz/faculty/teaching/mbchb209/_docs/volume_of_distribution_ppt.pdf
Nick
--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.-a-.auckland.ac.nz
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The following message was posted to: PharmPK
Neha,
Just to add a bit to Nick Holford's post - recognize that when he says
"dose" or "dose rate" it refers to the amount of drug that reaches the
systemic circulation. If bioavailability is 100%, then it's the same
as the
administered dose. If not, you need to reduce it to the amount that was
bioavailable.
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
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The following message was posted to: PharmPK
Neha
And a further point to consider, after those mentioned by Nick and
Walt is saturable elimination. Phenytoin being a teaching example
with saturable metabolism.
Cheers
Matt
Dr Matt Doogue
Clinical Pharmacologist / Endocrinologist
Flinders Medical Centre, Flinders University
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The following message was posted to: PharmPK
Hello,
If the rate of elimination follows the first order (drug is eliminated
by non saturable processes), Clearance shouldn't change (constant for
a drug) with the increase/decrease in the dose.
However, I have encountered drugs more with mixed order kinetics
(first order elimination at lower doses and zero (pseudo zero) order
at higher doses). This is due to the involvement of saturable
processes (metabolizing enzymes or transporters) in the elimination of
the drug.
In these cases you could find a decrease in clearance with dose. MM
kinetics would be helpful to describe this phenomenon.
As an example you can look at Itricanazole pK in rats...
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 2004, p. 1756 - 1762 by Jee
H Shin et al.
In fact looking at clearance at escalating doses will allow us to
delineate whether the drug get eliminated by any non-linear pathways.
Hope this would be helpful.
Thanks
Ravi Talluri Ph.D
Sai Advantium Pharma, Pune
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Hello,
In non compartmental analysis clearance can be calculated by
using the following equation
clearance =dose/AUC.
In case of IV dosing the dose can be taken as such (100 %
bioavailable). but for oral dosing the clearance is calculated based
on fraction of dose absorbed.
With regards,
V. Vijaya Bhaskar
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