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Hello ,
Could any of you help me out regarding this question I got from acolleague
the other day :
In general, how thight can one expect the correlation to be between
water/octanol distribution coefficiebt and degree of tissue-distribution
(Vd).
Eg: Assume log P values of -2.13, -1.98, -3.16 og -2, 87 is it possible to
predict or assume anything about degree of uptake into liver."
I suppose that the substances in question, except form the differing P
values, share some Physico-chemical (or pharmacological) qualities.
If any of you know any good references on the topic I would be very grateful.
regards
Nils Ove Hoem, Ph. D.
Associate professor,
Department of Pharmacology; School of Pharmacy
University of Oslo
POB 1068 Blindern
N-0316 Oslo
Norway
Phone: +47 22 856546
Mobile:+47 92681158
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[A few replies - db]
Date: Thu, 10 Feb 2000 00:31:34 -0700 (MST)
X-Sender: ml11439.-at-.pop.goodnet.com
To: PharmPK.at.boomer.org
=46rom: ml11439.at.goodnet.com (Michael J. Leibold)
Subject: Re: PharmPK Octanol/water coefficient and degree of=20
tissue-distribution
Nils,
=20 Octanol/water partiion coeficients have been correlated with
lipid solubility of beta-blockers. The more lipid soluble, the
higher the octanol/water partition coeficient. The octanol/water
partition was found to be associated with the degree of CNS side
effects of beta-blockers, which was assumed to a reflection of the
ability of beta-blockers to penetrate the lipid blood-brain barrier.
=20 Mike Leibold, PharmD, RPh
=20 ML11439.-a-.goodnet.com
---
Date: Thu, 10 Feb 2000 10:21:09 +0100
=46rom: "Theil, Frank-P. {PRNS~Basel}"
Subject: RE: PharmPK Octanol/water coefficient and degree of tissue-distri
bution
To: "'PharmPK.-at-.boomer.org'"
[Theil, Frank-P. {PRNS~Basel}] PharmPK - Discussions about Pharmacokinetics
=20 Pharmacodynamics and related topics
Dr. Hoem asked whether it is possible to predict tissue(liver):plasma
partition coefficients based upon octanol/buffer partition coefficients.
Dr. Hoem
>"In general, how thight can one expect the correlation to be between
>water/octanol distribution coefficiebt and degree of tissue-distribution
>(Vd).Eg: Assume log P values of -2.13, -1.98, -3.16 og -2, 87 is it
possible to
>predict or assume anything about degree of uptake into liver."
In several studies it has been shown that it is possible to predict the
tissue:plasma partition coefficients (PCs) of volatile organic chemicals
only from data on n-octanol:water PC or olive oil:water PC by using tissue
composition models developed recently by Poulin and Krishnan.
We have extended these tissue-composition models to drugs. The results of
this work is published in the first issue 2000 of J Pharm Sci.
Poulin P and Theil FP. A priori prediction of tissue:plasma partition
coefficients of drugs to facilitate the use of physiologically based
pharmacokinetic models in drug discovery. Journal of Pharmaceutical Sciences
89 (2000) 16-35.
The above paper demonstrates how to predict the tissue:plasma PC of
non-excretory and non-fatty tissues from olive oil:water PC. However, the
methodology can also be used for predicting the liver:plasma PC by
neglecting excretion processes in this tissue (i.e., prediction only by
considering binding to macromolecules and partitioning into lipid and water
fractions of liver). Note that, the predicted liver:plasma PC need to be
corrected for excretion processes, if data on hepatic extraction ratio are
available.
Patrick Poulin
=46rank-Peter Theil
=46. Hoffmann-La Roche, Ltd., Pharma Research Division
Basel, Switzerland
Other papers on the same subject are:
Poulin, P.; Krishnan K. 1995. An algorithm for predicting tissue:blood
partition coefficients of organic chemicals from n-octanol:water partition
coefficient data. Journal of Toxicology and Environmental Health. 46,
101-113.
Poulin P, B=E9liveau M, Krishnan K. 1999. Mechanistic animal-replacement
approaches for predicting pharmacokinetics of organic chemicals. In:
Toxicity assessments alternatives: methods, issues, opportunities. Eds. H.
Salem and S.A. Katz. Humana Press, Inc., Totowa, N.J., pp. 115-139.
Haddad S, Poulin P, Krishnan K. 2000. Relative lipid content as the sole
mechanistic determinant of the adipose tissue:blood partition coefficients
of highly lipophilic organic chemicals. Chemosphere, 40, 839-843.
Poulin P and Krishnan K. 1995. A biologically based algorithm for predicting
the human tissue:blood partition coefficients of organic chemicals. Human
and Experimental Toxicology 14: 273-280.
Poulin, P.; Krishnan K. Molecular structure-based prediction of the
partition coefficient of organic chemicals for physiological pharmacokinetic
models. Toxicology Methods 1996, 6, 117-137.
Poulin P and Krishnan K. 1996. A tissue-composition based equation for
predicting tissue:air partitioin coefficients of organic chemicals.
Toxicology and Applied Pharmacology 136:126-130
Poulin P and Krishnan K. 1996. A mechanistic algorithm for predicting
blood:air partition coefficients of organic chemicals with the consideration
of reversible binding in hemoglobin. Toxicology and Applied Pharmacology
136:131-137
---
=46rom: j.dejongh.-at-.lapp.nl
To: PharmPK.at.boomer.org
Date: Thu, 10 Feb 2000 10:37:56 +0100
Subject: Re: PharmPK Octanol/water coefficient and degree of=20
tissue-distribution
Priority: normal
Hello,
You may find the following of interest:
1. Poulin & Krishnan, Toxicol. Appl. Pharmacol (1996) 136: 126-137
2.. DeJongh et al. Arch. Toxicol. (1997) 72:17-25
Extrapolations to large MWs might be difficult.
I have a large list of literature on the subject, let me know if you want
it E-mailed.
Dr. Joost DeJongh
Leiden Advanced Pharmacokinetics & Pharmacodynamics (LAP&P) Consultants
Archimedesweg 31
2333 CM Leiden
The Netherlands
Phone: + 71 568 6920
fax: + 71 568 6972
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[Two replies - db]
Date: Fri, 11 Feb 2000 11:07:45 -0800
From: TM Gilman
Reply-To: tmgilman.aaa.attglobal.net
Organization: Simulations Plus, Inc.
X-Accept-Language: en
To: PharmPK.aaa.boomer.org
Subject: Re: PharmPK Octanol/water coefficient and degree of
tissue-distribution
1. Barton, P., et al., Drug-phospholipid interactions. 2. Predicting
the sites of drug distribution using n-octanol/water and
membrane/water distribution coefficients. J Pharm Sci, 1997. 86(9):
p. 1034-9.
2. Cheymol, G., et al., Pharmacokinetics of beta-adrenoceptor
blockers in obese and normal volunteers. Br J Clin Pharmacol, 1997.
43(6): p. 563-70.
3. Daniel, W., et al., Regional distribution of imipramine,
desipramine and specific [3H]desipramine binding sites in the rat
brain after acute and chronic treatment with imipramine. J Pharm
Pharmacol, 1991. 43(1): p. 31-5.
4. Heinzow, B., H. Lullmann, and L. Staib, Uptake and displacement of
[3H]-propranolol and [3H]-chlorpromazine in isolated, recirculating
perfused guinea-pig lungs. Arch Int Pharmacodyn Ther, 1988. 295: p.
211-20.
Thomas M. Gilman, Pharm.D., M.S. Biometry
Simulations Plus, Inc., gilman.aaa.simulations-plus.com
---
Date: 11 Feb 00 12:16:06 EST
From: Janusz Byczkowski
To: PharmPK.at.boomer.org
Subject: Re: [PharmPK Digest - Number 252]
Nils:
The very latest publication about "predictive" modeling of tissue/blood
partitioning from water/oil (water/Octanol) partitioning is:
Journal: Chemosphere
ISSN : 0045-6535
Volume : 40
Issue : 8
Date : 01-Feb-2000
pp 839-843
Relative lipid content as the sole mechanistic determinant of the adipose
tissue:blood partition coefficients of highly lipophilic organic chemicals
S Haddad, P Poulin, K Krishnan
You will find there referecnces to previous publications addressing issue of
tissue/blood partitioning.
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Nils-
Quality of the correlation between the 1-octanol/water partition coefficient
P and the pseudo-equilibrium tissue distribution depends on amphiphilicity
of the studied compounds. Ionization is also a factor to consider because it
may render the molecule amphiphilic (i.e. having the tendency to adsorb to
the membrane/water interface). If the compounds are not amphiphilic, their
tissue distribution is usually very well described by P. There are several
approaches available that delineate the form of equation relating the
tissue/blood partition coefficients PC of non-amphiphilic chemicals and P.
1. Abraham (J. Pharm. Sci. 1994, 83: 1450-1456 and the references therein)
used his solvation equation that was developed originally for homogeneous
media, to describe the tissue/blood partitioning.
2. Poulin and Krishnan (J. Pharm. Sci. 2000, 89:16-35 and the references
therein) assume that the vegetable oil (what is it, exactly?) has the same
lipophilicity as neutral lipids in tissues and predict PC a priori, without
any calibration (!), using the volume fractions of neutral lipids,
phospholipids, and water, as well as the fractions unbound in tissues (fut)
and in plasma (fup). The fractions unbound are more difficult to determine
experimentally than the total tissue concentrations, so they are usually not
measured/published. To estimate fut from available fup, the authors use a
rather daring assumption that the compounds bind also in tissues to the main
macromolecules (albumin, globulins, lipoproteins) which have the plasma
concentration two times higher than the tissue concentration.
3. DeJongh et al. (Arch. Toxicol. 1997, 72:17-25) use the relation between P
and the bilayer/water partition coefficient Pb in the form Pb=P^B, where B
is adjustable parameter. They did not explicitly consider protein binding in
development of the model.
4. We (Quant. Struct.-Act. Relat. 1999, 18:361-368) related both membrane
partitioning and protein binding to P as AxP^B (A and B are adjustable
parameters, different for partitioning and binding). This relation was
experimentally verified previously and is routinely used (as the Collander
equation) in construction of model-based QSAR models. Our model describes PC
as a function of P and lipid, protein, and water fraction simultaneously for
fat, brain, kidney, liver, muscle, lung, and heart.
The approaches 3 and 4 that use the 1-octanol/water partition coefficient P
as the only characteristics of compounds are easiest to use. All you need
is (1) to estimate P using the available software, e.g. ClogP or KowWin (the
latter has a web-accessible demo at
http://esc.syrres.com/interkow/kowdemo.htm/); (2) te get the form of the
equation from the publications above. If you are only interested in very
hydrophilic chemicals (as indicated by the logP values in your question) and
the chemicals are not amphiphilic, you can quite safely assume that they
will only be present in the aqueous phases. The dependence of logPC on logP
is sigmoidal. PC for hydrophilic chemicals are independent of P and can be
calculated as the ratio of the water volume fractions in tissue and in blood
(PC ~0.2 for fat, ~0.9 for liver and heart, ~0.96 - 0.99 for kindey, lung,
muscle, and brain).
I hope this will put the theme into a broader perspective.
Stefan
----
Dr. Stefan Balaz
Associate Professor
Department of Pharmaceutical Sciences
College of Pharmacy
North Dakota State University
108 Sudro Hall
Fargo, ND-58105-5055
vox +1-701- 231-7749
fax +1-701- 231-7606
e-mail balaz.-at-.prairie.nodak.edu
http://www.ndsu.nodak.edu/instruct/balaz
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