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Hi,
I have a question regarding CL and Vd. If a drug has a large volume
of distribution and high clearance, can we assume that part of the
high CL is due to tissue distribution. I mean is uptake into tissues
should be included to explain high CL? Remember in compartmental
analysis we have a distribution phase and an elimination phase and in
CL calculation we use AUC . In that case we are including data from
the distribution phase in the AUC for CL. What about highly
lipophilic drugs which may stay in tissues long time? Is their tissue
distribution should be included in the CL calculation? Any good
comments are welcome. Thanks.
Geo Thompson
gnadakal5.at.yahoo.com
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The following message was posted to: PharmPK
AUC (0 to infinity) is determined only by the dose and CL/F.
Distribution
clearance has no effect at all.
--
Nick Holford, Dept 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)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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The following message was posted to: PharmPK
Geo,
Clearance and Volume of Distribution are considered 'independent'
pharmacokinetic parameters. In effect, this means that they have no
influence one another.
However, the term 'independent' is sometimes misconstrued since
Clearance
does depend on blood flow to- and intrinsic clearance of the clearing
tissue/organ and sometimes on plasma drug-protein binding (depending
upon
the clearance characteristics of your drug). Similarly, Volume of
Distribution depends on the volume of blood, the volume of the tissue(s)
compartment(s), plasma drug-protein binding, and tissue drug binding.
Hank
H.J. Pieniaszek, Jr., Ph.D., FCP
HPP Consulting & Services, Inc.
1904 Poole Road
Darlington, MD 21034
410-457-0305 (voice and fax)
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Geo,
To answer your question, we have to refresh the concepts of volume of
distribution Vd and clearance CL.
Both Vd and CL are primary PK parameters. Vd is determined by plasma
volume, plasma protein binding, tissue volume and tissue protein
binding for the drug. CL normally consists of both metabolic and
renal clearances. Renal clearance is determined by glomerular
filtration rate, proximal tubule reabortption and active excretion by
transporters. Metabolic clearance is normally determined by plasma
protein binding, hepatic blood flow and the intrinsic clearance for
the drug. Under certain assumptions, when you calculate CL, CL=Dose/
AUC. Vd has no impact on the value of CL. Volume of distribution and
clearance are independent of each other. In the case that there is
"deep deposit" conpartment, for the terminal phase, the elimation is
a re-distribution rate limited.
PZhou
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The following message was posted to: PharmPK
Geo,
I noted a few very good responses to this question. Let me give you
my spin. Consider the following two relationships, where terms refer
to system state at time, t:
Rate of Elimination = (Clearance) x (Plasma Concentration)
Amount of Drug in Body = (Volume of Distribution) x (Plasma
Concentration)
One can see both Clearance and Volume of Distribution are
proportionality constants, viz-a-viz Rate of Elimination and Amount
of Drug in Body, respectively. In a generalized mathematical sense,
they are independent of one another. However, they both have
dependency on a few biological factors, e.g., plasma binding.
For further discussion, I recommend Rowland & Tozer, "Clinical
Pharmacokinetics," any edition.
Harold Boxenbaum, Ph.D.
Pharmaceutical Consultant
Arishel Inc.
14621 Settlers Landing Way
North Potomac, MD 20878-4305
(P) 301-424-2806
(C) 240-422-0525
(F) 301-424-8563
Email: harold.aaa.arishel.com
Website: www.arishel.com
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