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in our lab we collect data from children receiving the enzyme
asparaginase for the treatment of ALL.
=46or a number of patients, the initial activity up to some hours after
the end of infusion is very high resulting in a Vd which is about 1/2
the plasma volume.
We excluded errors deriving from sample collection and the assay is
validated in the respective range.
Is there a physiological explanation for this or is anything similiar
described in the literature for other drugs ? Any comments on this would
Dr.rer.nat. Georg Hempel
Klinik und Poliklinik f=FCr Kinderheilkunde
- Paediatrische Haematologie/Onkologie -
D-48129 Muenster, Germany
Phone: +49 251 83-56741
=46ax: +49 251 83-47828
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Vancomycin multicompartment pharmacokinetics has been described
with both two and three compartment models. The three compartment model
has a relatively small Vc associated with a very short distribution phase
half-life ( 7min). The Vc estimated with three compartment kinetics is in
the area of 0.13 L/Kg, versus the 0.2-0.6 L/kg estimated with two compartment
pharmacokinetics with an initial distribution half-life of 1.6-3.6 hours.
An obvious possibility for your drug could be an initial rapid distribution
phase where the initial Vc would be described as:
P,A,B are the Y intercepts of the alpha, beta and gamma distribution
and elimination phases. If the initial distibution phase is very rapid, then
P will be higher and the Vc will be very small. Also, it can be seen that
three compartment pharmacokinetis with an intial rapid distribution phase
versus the standard two compartment treatment, results in a decrease in
the estimated Vc since another term is added to the denominator of the two
compartment equation for Vc:
Using a two compartment model, the greater the K12 microconstant is
relative to K21, the smaller the Vc:
Vc= Vss[k21/(k21+ k12)]
So, it would seem that the more rapid the distribution phase, the
higher the microconstant for transfer out of the central compartment, and
the smaller the Vc.
Physiologically, this could be complicated for an enzyme such as
asparaginase and could involve rapid tissue binding.
Mike Leibold, PharmD, RPh
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[Two replies - db]
Date: Mon, 13 Dec 1999 08:52:20 +0100
Subject: Re: PharmPK Vd smaller than plasma volume
Just remind that in patients with ALL, blood has to be taken through a
central catheter (in general with a double lumen) that is also used for
drug infusion. Are you sure that no sample contamination occurred, which
could explain your results through artificially elevated initial
concentrations ? Can you consider that a fraction of the infused enzyme
gets retained in the area of catheter aperture in the blood stream, and
that enriched blood is then sampled at the initial sampling times ?
Thierry BUCLIN, MD
Division of Clinical Pharmacology
University Hospital CHUV - Beaumont 633
CH 1011 Lausanne - SWITZERLAND
Tel: +41 21 314 42 61 - Fax: +41 21 314 42 66
Date: Mon, 13 Dec 1999 10:59:06 -0700
From: "David Nix, Pharm D."
Organization: College of Pharmacy
Subject: Re: PharmPK Re: Vd smaller than plasma volume
RE: Distribution volume less than plasma volume.
The original question pertained to possible reasons for having a volume
of distribution less than plasma volume. From a purely theoretical
basis, such a volume is not reasonable. In any PK analysis, one must
assume homogeneous concentrations (within compartments (compartmental
modeling) or at least well mixed distribution sites. I would propose
that perhaps the sampling was schedule was too rapid to ensure adequate
mixing. This could occur in cases where a sample is drawn immediately
after an IV bolus or during an infusion. The site of sample collection
relative to drug administration is also important to consider.
Distribution takes some time and is not instantaneous as we must assume.
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