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Dear Members,
I have been searching for a drug that is neutral (zwitter ion) at a
physiological pH and has low protein binding characteristics (<30%).
The drug has to be available for clinical use.
If you could think of some examples, I would really appreciate your
help.
Regards,
Khalid Alkharfy, Pharm.D., Ph.D.
Assistant Professor of Clinical Pharmaceutical Sciences
Department of Clinical Pharmacy
School of Pharmacy
King Saud University
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Khalid-
Acyclovir and ganciclovir are two neutral drugs (but not zwitter ions)
that have low protein binding (acyclovir: 9-33%; ganciclovir: 1-2%)
Tom Tarnowski
Thomas L. Tarnowski, Ph. D.
Project Team Leader, Bone Protective Agent for Osteoporosis
Dept. Head, Drug Metabolism and Pharmacokinetics
Roche Palo Alto
3431 Hillview Avenue, Palo Alto, CA 94304
email tom.tarnowski.-at-.roche.com
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You may wish to consider tetracycline which is zwitterionic in nature,
electroneutrality at about pH 5. Athough it is about 65% protein
bound, that is not clinically significant. Other tetracyclines may be
more appropriate still.
Lawrence H. Block, Ph.D.
Professor of Pharmaceutics
Graduate School of Pharmaceutical Sciences
and Mylan School of Pharmacy
Director, Duquesne University Center for Biotechnology
437 Mellon Hall of Science
Duquesne University
Pittsburgh, PA 15282-1504
USA
Tel.: 412.396.6362
Fax: 412.396.5599
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Dear khalid, cephalexin is one which is zwitterionic and with 14%
plasma protein binding.
hope this will helps.
jayasagar gundu
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Der Dr Alkharfy,
Pease consider:
Isoniazid - not protein bound
Thiamazole - not protein bound
Fluconazole - 12%
Ganciclovir - <10% ( pKa1= 2.2 and pKa2>9)
Acyclovir - <30% (similar pKa's as Ganciclovir)
sincerely
Kazimierz H. Kozlowski, Pharm. D.
Laboratory of Pharmacokinetics
The Children's Memorial Health Institute
04-736 Warsaw, POLAND
E-mail: khkoz.at.czd.waw.pl
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Dear Dr Tarnowski.,
I would like to know if really ganciclovir&acyclovir
are not zwitterionic drugs in blood serum (pH 7.4)?
What does means "zwitterion" werb in chemistry,
and what is concequence on drug distribution?
Ganciclovir has two pKa (pKa1=2.2, pKa2=9.4)
Acyclovir has two pKa (pKa1=2.27, pKa2=9.25)
Ganciclovir have typical value in population TVVD which
aproximates total body water (not protein bound drug)
in infants. However, correlation between individual
total body water and individual VD is not such good.
I believe, that ganciclovir is distributed according to
differences in pH in particular compartments or body organs.
sincerely
Kazimierz H. Kozlowski, Pharm. D.
Laboratory of Pharmacokinetics
The Children's Memorial Health Institute
04-736 Warsaw, Poland
E-mail: khkoz.aaa.czd.waw.pl
Warsaw, 30 April, 2003, 11:40
[Zwitter ions occur when a molecule has two pKa's and in neutral pH
solution both are ionic (one positive and the other negative). Thus
although the molecule may be neutral it is quite polar and its
distribution would be limited as any polar molecules. - db]
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Dear Dr. Kozlowski,
The term "zwitterion" means a molecule that simultaneously has both a
positively charged group and a negatively charged group.
Ganciclovir (pKa1=2.2, pKa2=9.4): In very acidic medium (pH less than
2.2) ganciclovir is protonated and therefore has a single positive
charge. In solutions of pH between 2.2 and 9.4 (such as pH 7.4)
ganciclovir is mainly neutral, with no charged groups. It is not
zwitterionic. In strongly basic solution (pH greater than 9.4)
ganciclovir is deprotonated and has a single negative charge.
The corresponding situation exists for acyclovir.
Despite its neutrality at physiological pH values, ganciclovir is small
and polar and is somewhat resistant to crossing lipid membranes. The
low bioavailability of ganciclovir is one kind of manifestation of
this. The low distribution into cerebrospinal fluid, where it is only
24 to 70% of the corresponding plasma concentrations, is further
evidence of this effect. Note also that within cells ganciclovir
becomes mono, di- and tri-phosphorylated (it is the triphosphate that
interferes with viral DNA synthesis).
Since the pH of most tissues is in the neutral range and generally
quite far from the pH values required to produce charged species from
ganciclovir, the small difference in organ pH values within the neutral
range seem unlikely to account for significant differences in organ
distribution of ganciclovir.
Kind regards,
Thomas L. Tarnowski, Ph. D.
Dept. Head, Drug Metabolism and Pharmacokinetics
Roche Palo Alto
3431 Hillview Avenue, Palo Alto, CA 94304
Phone: (650) 852-3182
FAX: (650) 852-6428
email tom.tarnowski.-at-.roche.com
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