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Hi all,
Some drugs have 2 or 3 pKa values. In such cases what pka will be used to calculate the ionized and non-ionized species at different pH ??
regards,
raghav.
[You might find the second and third link on http://www.boomer.org/c/d1/
useful - db]
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Hi Raghav,
Comprehensive Medicinal Chemistry (2nd ed) contains a great reference (2007).
Volume 5, Physicochemical tools in Absorption, Distribution, Metabolism, Excretion, and Toxicity
5.16 - Ionization Constants and Ionization Profiles, Pages 357-397, J.E.A. Comer
http://www.sciencedirect.com/science?_ob=RefWorkIndexURL&_idxType=TC&_ cdi=41183&_refWorkId=388&_explode=1431000034,&_alpha=&_acct=C000 024058&_version=1&_userid=494590&md5=31bc7bf96157165a0e6462ffd5d1ddf 0&refID=1431000038#1431000038
Unfortunately there isn't a short answer as there are different calculations you will use depending on whether the drug is an acid, base, ampholyte, etc.
I am guessing you won't be able to use the links, but you should be able to track down the reference.
Best Wishes,
Ian
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Great resource Ian, thanks.
Raghav,
one also has to consider the main compartment of its absorption and other characteristics. We tend to want to break things down into rules that are applicable under all situations when, in fact, they are situational. What is the exact situation that you are trying to define with a general question. Specific questions tend to yield specific answers.
Sanjeev Thohan, PhD
SARx Consulting
SARxconsult.at.Gmail.com
http://www.linkedin.com/in/sanjeevthohan
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Dear Raghav,
You wrote:
Some drugs have 2 or 3 pKa values. In such cases what pka will be used to calculate the ionized and non-ionized species at different pH ??
The short answer is: ALL of them!
Many in academia and industry have long worked with the misconception that at any pH, a multiprotic molecule exists as a single species that is either acidic, basic, or neutral. This is completely false! What actually happens is that as pH changes, there is a shifting equilibrium among ionized microspecies. Take, for example, cetirizine, which has three ionisable groups: one carboxyl and two aliphatic amines. The three pKas are 7.98, 2.90, and 2.12 (Tam KY, Quere L. "Multivawelength Spectrophotometric Resolution of the Micro-Equilibria of Cetirizine" Anal Sci. 2001; 17:1203-1208.)
This molecule can exist in 8 different states ranging from fully deprotonated (at pH > about 11) to fully protonated (at pH < about . Between the states of 100% protonated and 100% deprotonated, an equilibrium will be established among several microspecies with protonation/deprotonation at different atoms on the molecule. This is why our ADMET Predictor pKa predictions use microspecies equilibrium calculations (including quantum level descriptors developed from rapidly calculated atomic partial charges) to achieve accurate pKa predictions, rather than the earlier approach with Hammett & Taft sigma constants.
Check out the detailed explanation on our web site http://www.simulations-plus.com then click on the ADMET Predictor logo, then on the link to "Biopharmaceutical and Physicochemical Models", then on the link for "pKa".
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
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Hi Thohan,
After your reply , i keep the original problem from which my previous question has araised !!!!!!
We had a compound with amide funcitonal group (also morpholine) and when i predict the pka using software end up with 4 pka. The predictions form the software as follows -
Amide - acidic pKa : 18
Morpholine - basic pKa : ~ 8.5
Amide - basic - pKa : - 2.5
Another centre basic - pKa : ~ 6.5
I am actually trying to predict the tissue distribution of this compound from in vitro data (Log D, pka and fu etc., ) and while doing so i got doubt which pka to use in the equations !
(All these things came up because when rat PK was performed for this drug the IV clerance is 69 mL/min/kg and the bioavailability is 70 %. (blood partitioning and other assays where this type of problem can be probed were tried for this compound) We couldnt find the disconnect between clerance and bioavailability. microsomal metabolic stability indicate that the compound is highly stable , stable in hepatocytes, not renally excreted, not excreted in feces too)
what could be the reason for high bioavailability although high clearance is observed in vivo.
We thought that tissue accumulation might be one of the reason. but there is no significant increase in exposures or Cmax after 28 day tox study.
And finally i am of opinion that the difference in absorption of ionized and unionized drug in plasma (to different tissues, when given IV) and absorption at different sites of GIT (when given orally) would lead to these differences (high clearance from plasma and high bioavailability !!!!!!!!!!!!!!
With best regards,
Raghav,
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Raghav
explain me what do you understand by acidic pKa and basic pKa ? For me a pKa is the dissociation constant of an acid ?
Kind regards
Dr. R. KINGET
University of Leuven
Belgium
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The following message was posted to: PharmPK
He's talking about the pKa of a free acid or the conjugate acid of a base.
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Thanks Raghav, an interesting compound.
With a tremendous amount of respect to our colleagues in the in vitro and simulations aspect of things, we cannot predict everything and should not expect to. There is no substitute for an in vivo study
We have compounds in the literature whereby we show metabolic stability due to precipitation and re-solubilization upon assay time point termination with organic solvents. Also phase II direct conjugated compounds tend to be stable in phase I microsomal assays. Have you tried multiple species microsomal/hepatocytes? planned in vivo in dogs? - maybe a rat specific issue??
WRT to hepatocytes, have you tried fresh hepatocytes or cryopreserved? any differences
In rats, have you been able to get liver levels of the drug? Muscle levels of the drug (thigh muscle sampling)
Have you tried a hepatic portal infusion to determine if it either accumulation of the drug in the liver or a metabolic process resulting in a very high first pass effect (propranolol). What was the oral %F at escalating doses? does it change? how high did you go for IV and PO doses. What were the volumes, calculated Vd or Vss?
Do you have multiple dose PK?
Comprehensive metabolite identification with a full scan followed be specific extracted ion analysis from predictive MRM's of parent, metabolite and related compounds from a theoretical met-ID scenario. This will allow you to assess whether there is a primary or multiple secondary metabolites in the absence of a radiolabel tracer.
Thanks again, loads of questions.....
sanjeev
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Dear colleague,
One possible explanation of this disconnect i.e. "the high absolute oral bioavailability in rats despite high in vivo clearance" would be the presence of extrahepatic / extra-gut metabolism. Have you checked blood and plasma stability of this drug? From experience , we have a couple of examples where we observed such disconnect and was explained by the plasma instability.
Another explanation would be related to the determination of AUC and sensitivity of the analytical method. For example, if the PK profile after iv was not well characterized due to a low dose given and/or low assay sensitivity you may underestimate AUC and therefore overestimate intravenous clearance (CL = Dose/AUC).
Tissue accumulation and distribution should not have an impact on oral bioavailability in my opinion.
Kind Regards, Youssef.
Dr Youssef Hijazi
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