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The following message was posted to: PharmPK
I have taught the concepts of lipid solubility as being distinct from state
of ionization.
When a drug is in an environment in which the pH of the environment is
equal to the pKa of the drug the drug is 50% ionized and 50% nonionized. I
was told that for weak acids such as aspirin, when the pKa and pH of the
environment the drug has 50% lipid solubility. I have been unable to
confirm this and wonder if any of you had references I can use to explore
this concept. This person is equating lipid solubility with ionization
which I have treated as separate independent properties.
If one considers a drug that is 100% lipid soluble and is interested in how
much is able to cross the plasma membrane, then only 50% is able to do so
because only 50% is non-ionized. If a drug has very low solubility (e.g. a
polar compound with a lipid to water partition coefficient of around 10 I
don't see how this can be at 50%. Despite being ionized, there should not
be, in my opinion, be a change in the lipid solubility. Since the
individual who told this to me was a Ph.D. Pharmacologist, I did not feel
it appropriate to challenge without further study. I have not been able to
come across any info on this and would appreciate any references to help me
get a better understanding.
Clifford Ferguson M.D.
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[Three replies - db]
From: "Steve Durfee"
Date: Thu, 27 Sep 2001 14:59:58 -0600
To: david.at.boomer.org
Subject: RE: PharmPK Ionization and Lipid Solubility
The following message was posted to: PharmPK
As a chemist, I agree with you. According to the law of mass action, lipid
solubility, aqueous solubility and acid dissociation are controlled by
different equilibrium constants. None of them can be derived from the
other. Although there are underlying properties that promote aqueous
solubility and lipid solubility (such as molecular weight or van der Waals
radius), there are also properties that are distinct (such as ability to
hydrogen bond or dipole/dipole interactions).
To calculate the concentrations for a mixed system of a weak acid, an
aqueous phase and a lipid phase, it would be necessary to invoke all three
constants to calculate the concentration (actually the activity) of any
individual component.
Steve Durfee, Ph.D.
---
From: Seetal Dodd
Date: Fri, 28 Sep 2001 09:40:09 +1100
To: david.aaa.boomer.org
Subject: Re: PharmPK Ionization and Lipid Solubility
Dear Clifford,
A reference you might find useful is:
Manners CN, Payling DW and Smith DA. Distribution coefficient, a convenient
term for the relation of predictable physico-chemical properties to metabolic
processes. Xenobiotica (1988), 18(3): 331-350
Best regards,
Seetal
Dr Seetal Dodd
Research Fellow
Department of Pharmaceutics,
Victorian College of Pharmacy, Monash University
381 Royal Parade, Parkville, Victoria 3052
Australia.
Tel: +61 3 9903 9053
Fax: +61 3 9903 9583
---
From: "Newman, Edward"
Date: Thu, 27 Sep 2001 15:51:27 -0700
To: david.at.boomer.org
Subject: RE: PharmPK Ionization and Lipid Solubility
Equating lipid solubility to extent of ionization sounds screwy to me.
First of all deprotonation and protonation of ordinary proton acids and
bases in water is an exceedingly fast equilibrium. You cannot extract the
non-ionized species and leave behind the ionized species; at the pKa half of
whatever is left in the aqueous phase will be ionized. What you get is the
lipid partitioning of the ionized species (low), the lipid partitioning of
the neutral species (whatever it is), and the ionization in the aqueous
phase, all in equilibrium.
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The following message was posted to: PharmPK
Dear Clifford,
In my opinion you are right to say that lipid solubility and
ionisation are two different things. In fact the ionized compound is
more soluble in water, but it's no right in my opinion to say that if
50% of the compound is non ionized, 50% of the that form will cross
the membrane. So I do agree with your opinion and made it confirm
with one of my lab's Ph-D. Solubility and ionization are linked but
not strictly proportional.
I hope this helps
=46 Lagarce
=46r=E9d=E9ric Lagarce
ph-D Student
INSERM-ERIT-M 0104 ing=E9ni=E9rie de la vectorisation particulaire
10 rue A Boquel - Bat IBT - 49100 Angers
Tel Prof : (33) 2 41 73 58 51
mobile : 06 83 40 43 39
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The following message was posted to: PharmPK
Clifford,
What you have are two competing equilibrium systems -
drug in oil equilibrated with drug in water
drug in water equilibrated with ionized form
So, the equations would look like -
log K(distribution constant) = log drug in oil - log unionised drug
in water
pKa(dissociation constant) = (pH - log ionised drug) + log
unionised drug in water
by mass balance total drug added = drug in oil + drug in water unionised
+ drug ionised
or (total drug - drug in oil) = (drug in water
unionised + drug ionised)
= drug in water unionised (1 +
pH/pKa)
so log K = log drug in oil - log (total drug - drug in oil) + log
(1 + pH/pKa)
rearrange log K = log (1 + pH/pKa) - log (total drug/drug in oil - 1)
or total drug/drug in oil = 1 + (1 + pH/pKa)/K
You cannot predict log K from pKa and pH - you will need to independently
measure the drug in oil content. You can make some assumptions regarding
the expected distribution constant, plug it into the above.
If the drug is highly lipophilic (ie mostly in oil), the pH really isn't
important as the second term is ca. zero. You can plug guestimates of pH
and K in here to get a feel for the effect. I don't know what K to expect
for a weak acid.
Hope this helps
Norma
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