Back to the Top
Dear all
I would like to have some information about the rate of absorption of a
compound which is a zwitterion, after administration by gavage. For
instance, gatifloxacin has -COOH and -N in its molecule so it has two
pka. What about its ionization when it is in the stomach? Which is the
predominant state ?
I appreciate your input.
Leandro Tasso, M. D.
Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Faculdade de Farmacia
Back to the Top
The following message was posted to: PharmPK
Dear Dr. Tasso,
Our ADMET Predictor(tm) software provides the following *estimates* for
gatifloxacin ionization:
pKas: Bases at 8.75 and 7.09, acid at 4.82
At pH 2, 100% ionized, dominated by +2 species, with the
following microspecies distribution:
~58% with the piperazine NH and the aromatic N
protonated
~34% with the piperazine NH and the piperazine N
protonated
~8% with all 3 Nitrogens protonated and the OH
deprotonated
At pH 7.4: 100% ionized, dominated by +1 and 0 species, with the
following microspecies distribution:
~2% with the piperazine NH and the piperazine N
protonated and the OH deprotonated
~30% with the piperazine NH and the aromatic N
protonated and the OH deprotonated
~35% with the piperazine NH protonated and the OH
deprotonated
~30% with the aromatic N protonated and the OH
deprotonated
~0.8% with the piperazine N protonated and the OH
deprotonated
If you'd like to see graphics depicting the above information, send me
an e-mail (it's much easier than reading the text!).
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.-at-.simulations-plus.com
Back to the Top
The following message was posted to: PharmPK
Dear Dr Tasso,
the experimental pKa values of gatifloxacin are 6.0 (pKa1) and 9.2
(pKa2).
References:
1) http://www.unb.br/fm/disciplinas/123676/Prost.pdf
2) Sorgel F, Kinzig M, Pharmacokinetics of gyrase inhibitors, Part 1:
Basic chemistry and gastrointestinal disposition. Am J Med. 1993 Mar
22;94(3A):44S-55S. Review.
The pKa1 refers to the COOH-group and pKa2 refers to the N4' of the
piperazine ring. To the best of my knowledge the N1 is not
protonated, because it is part of an aromatic 10-pi-electron system
and shares an capto-dative electronic interaction with the C=O group
at the C4.
Consequently, gatifloxacin has primarily (>99%) charge +1 at pH < 4.
At its isoelectric point at pH 7.6, most of the gatifloxacin
molecules are zwitter-ions (net charge 0) and a small portion are in
the non-zwitter-ionic form with charge 0.
I have no experience with gavage. The average Tmax of gatifloxacin
reported in literature for healthy volunteers is between 1.0 and 1.7
h. Most quinolones have an average Tmax after oral administration of
less than 2 h (exceptions: difloxacin, grepafloxcin, sparfloxacin,
temafloxacin, and tosufloxacin). For an in-house dataset after an
oral dose of gatiflxoacin in healthy volunteers, I got a median half-
life of absorption of 26 min for gatifloxacin. I believe that the
oral absorption of quinolones is rather complex, since solubility,
protonation / deprotonation, and the presence of drug transporters
possibly all contribute to the absorption process.
In general quinolones have rather fast absorption half-lives (range:
about 10 min - 60 min). However, I am not sure, if it is possible to
identify the influence of each chemical species.
Hope this helps.
Best regards
Juergen
---
Juergen Bulitta, M.Sc.
Research Scientist
IBMP - Institute for Biomedical and Pharmaceutical Research
Paul-Ehrlich-Strasse 19
90562 Nurnberg - Heroldsberg
Germany