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Hello All!!
Our Group is studying the tissue pharmacokinetics of various
classes of compounds.
We normally follow the standard procedure of making the 20%
homogenate in phosphate buffer(pH 7.4).
However, we have observed very low tissue penetration with poorly
water soluble compounds (water solubility < 1 mg/ml).
Is it OK to use the above mentioned standard procedure or we need
to change the method for poorly soluble drugs.
We would appreciate any comments.
Thanks : Sandeep
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Dear Sandeep
in our hands the use of ethanol/water mixtures 1:4 up to 4:1 (v/v) for
homogenisation improves the recovery rate for poorly
water soluble compounds.
Kind regards,
Gerhard
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[A few replies - sorry about the interruption in the discussion - db]
From: GLDrusano.at.aol.com
Date: Wed, 31 Jul 2002 08:11:29 EDT
Subject: Re: PharmPK Re: Tissue Pharmacokinetics
To: PharmPK.-at-.boomer.org
MIME-Version: 1.0
Status: O
Hi!
This is a classical problem. The issue was highlighted in the early
80's by Otto Cars, who studied beta-lactam antibiotics. Cell
penetration for these drugs is 5% or less. When tissue is ground, as
you describe, it takes the 80% of the tissue volume that has
approximately 5% of the drug and mixes it with the ExtraCellular
Fluid, where the other 95% is. The result is an approximate 4-5 fold
dilution.
Dr. Cars was studying penetration into rabbit muscle and solved the
problem by freeze drying strips of muscle after weighing them he then
reconstituted them back to their wight in PBS with differing drug
concentrations and performed a bioassay. The results were exactly
what were expected. Being a bioassay, this will not work for a drug
with an active metabolite.
The exact opposite problem is seen with fluoroquinolones. Here, the
drugs penetrate quite well into cells. If the aim is to understand
the amount of drug in the ECF, grinding releases intracellular drug
into the ECF, giving a falsely high value (if you care about the
ability of the drug to kill extracellular pathogens).
Hope this provides some help.
All the best,
George Drusano
---
From: "Carson, Mary C"
To: "'PharmPK.-at-.boomer.org'"
Subject: RE: PharmPK Re: Tissue Pharmacokinetics
Date: Wed, 31 Jul 2002 10:09:59 -0400
MIME-Version: 1.0
Status: O
I suggest you look at methods used by residue chemists for food safety
monitoring and related studies. Phosphate buffer is almost never used to
extract drug residues from liver, kidney, muscle or other tissues. More
common solvents are ethyl acetate, acetonitrile, or sometimes aqueous acidic
solutions.
Mary Carson
FDA Center for Veterinary Medicine
The opinions expressed in this message are those of the author and do not
reflect the policies of the FDA.
---
From: "Prof. Walter Wolf"
Subject: Re: PharmPK Re: Tissue Pharmacokinetics
To: PharmPK.at.boomer.org
Cc: Multiple recipients of PharmPK - Sent by,
wwolfw.aaa.usc.edu
Reply-to: wwolfw.aaa.usc.edu
Organization: University of Southern California
MIME-version: 1.0
X-Accept-Language: en
Status: O
Sandeep:
Can you please clarify what you mean by the term "Tissue
Pharmacokinetics"? In my understanding, this term suggests that you are
measuring the pharmacokinetics of a drug at the tissue level. What you
appear to be describing below, using a homogenate, suggests that what
you are studying is the metabolism of your drug in cell extracts. That
information may be useful for understanding the pharmacokinetics of
drugs, but can not be construed by any means as being "tissue
pharmacokinetics".
Also, what do you mean by "low tissue penetration"? Across what barrier?
And when you say: "standard procedures", can you advise what reference
describes such procedures? Standard for what?
Professor Walter Wolf, Ph.D.
Distinguished Professor of Pharmaceutical Sciences
Director, Pharmacokinetic Imaging Program
Department of Pharmaceutical Sciences, School of Pharmacy
University of Southern California
1985 Zonal Ave., Los Angeles, CA 90089-9121
E-Mail: wwolfw.at.usc.edu
---
From: "fabrice.lagrange"
To: "=?utf-8?Q?PharmPK?="
X-XaM3-API-Version: 3.2 (B24)
X-type: 0
X-SenderIP: 194.65.100.7
Status: O
I used the same procedure and observed similar results.
Differences between compound or tissue, in tissue penetration,
can be observed using the dialysis cell of bickel.
Your sincerely,
F. Lagrange
Fabrice Lagrange
37 Avenue du Stade
66350 TOULOUGES
France
E-mail:fabrice.lagrange.-a-.laposte.net
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