Skip to main content
SpringerLink
Log in

pH Partition Theory

  • Living reference work entry
  • First Online:
The ADME Encyclopedia

  • 188 Accesses

Synonyms

pH partition hypothesis; pH partitioning; Theory of nonionic diffusion; Nonionic diffusion; Distribution coefficient; log D; Ion trapping

Definition

The pH partition theory (or pH partition hypothesis, also referred to sometimes as the theory of nonionic diffusion) was conceived during the first half of the twentieth century upon prior observations which suggested that only lipophilic chemical species could cross lipoid biological barriers. The theory states that since most drugs are weak electrolytes, only the nonionized species will be able to permeate across biological barriers; subsequently, weak bases would preferably distribute to acidic body compartments, whereas weak acids would preferably remain in basic ones. The tendency of an ionizable molecule to accumulate in those cells or organelles where the ionized species predominates is known as ion trapping.

While the pH partition theory provides a useful general approximation to anticipate diffusional solute transport...

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  1. Schanker LS. On the mechanism of absorption of drugs from the gastrointestinal tract. J Med Chem. 1960;2:343–59.

    Article  CAS  Google Scholar 

  2. McCormack K, Brune K. Classical absorption theory and the development of gastric mucosal damage associated with the non-steroidal anti-inflammatory drugs. Arch Toxicol. 1987;60:261–9.

    Article  CAS  Google Scholar 

  3. Ito S, Ando H, Ose A, Kitamura Y, Ando T, Kusuhara H, et al. Relationship between the urinary excretion mechanisms of drugs and their physicochemical properties. J Pharm Sci. 2013;102:3294–301.

    Article  CAS  Google Scholar 

  4. Gerweck LE, Vijayappa S, Kozin S. Tumor pH controls the in vivo efficacy of weak acid and base chemotherapeutics. Mol Cancer Ther. 2006;5:1275–9.

    Article  CAS  Google Scholar 

  5. Raghunand N, Mahoney BP, Gillies RJ. Tumor acidity, ion trapping and chemotherapeutics. II. pH-dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agents. Biochem Pharmacol. 2003;66(7):1219–29.

    Article  CAS  Google Scholar 

  6. Ufuk A, Somers G, Houston JB, Galetin A. In vitro assessment of uptake and lysosomal sequestration of respiratory drugs in alveolar macrophage cell line NR8383. Pharm Res. 2015 Dec;32(12):3937–51.

    Article  CAS  Google Scholar 

  7. Kaufmann AM, Krise JP. Lysosomal sequestration of amine-containing drugs: analysis and therapeutic implications. J Pharm Sci. 2007;96:729–46.

    Article  CAS  Google Scholar 

  8. Anderson PO, Sauberan JB. Modeling drug passage into human milk. Clin Pharmacol Ther. 2016;100(1):42–52.

    Article  CAS  Google Scholar 

  9. Overton E. Osmotic properties of cells in the bearing on toxicology and pharmacology. Z Physik Chem. 1887;22:189–209.

    Google Scholar 

  10. Meyer H. On the theory of alcohol narcosis I. which property of anesthetics gives them their narcotic activity? Arch Exp Pathol Pharmakol. 1899;42:109–18.

    Article  Google Scholar 

  11. Dearden JC. Partitioning and lipophilicity in quantitative structure-activity relationships. Environ Health Perspect. 1985;61:203–28.

    Article  CAS  Google Scholar 

  12. Fieser LF, Richardson AP. Naphthoquinone antimalarials II. Correlation of structure and activity against P. Iophurae in ducks. J Am Chem Soc. 1948;70:3156–65.

    Article  CAS  Google Scholar 

  13. Fieser LF, Ettlinger MG, Fawaz G. Naphthoquinone antimalarials. XV. Distribution between organic solvents and aqueous buffers. J Am Chem Soc. 1948;70:3228–32.

    Article  CAS  Google Scholar 

  14. Travell J. The influence of the hydrogen ion concentration on the absorption of alkaloids from the stomach. J Pharmacol Exp Ther. 1940;69:21–33.

    CAS  Google Scholar 

  15. Shore PA, Brodie BB, Hogben CA. The gastric secretion of drugs: a pH partition hypothesis. J Pharmacol Exp Ther. 1957;119:361–9.

    CAS  PubMed  Google Scholar 

  16. Shawahna R, Rahman N. Evaluation of the use of partition coefficients and molecular surface properties as predictors of drug absorption: a provisional biopharmaceutical classification of the list of national essential medicines of Pakistan. Daru. 2011;19:83–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Bhal SK, Kassam K, Peirson IG, Pearl GM. The rule of five revisited: applying log D in place of log P in drug-likeness filters. Mol Pharm. 2007;4:556–60.

    Article  CAS  Google Scholar 

  18. Andrés A, Rosés M, Ràfols C, Bosch E, Espinosa S, Segarra V, Huerta JM. Setup and validation of shake-flask procedures for the determination of partition coefficients (logD) from low drug amounts. Eur J Pharm Sci. 2015;76:181–91.

    Article  Google Scholar 

  19. Kokate A, Li X, Jasti B. Effect of drug lipophilicity and ionization on permeability across the buccal mucosa: a technical note. AAPS PharmSciTech. 2008;9:501–4.

    Article  CAS  Google Scholar 

  20. Kokate A, Li X, Singh P, Jasti BR. Effect of thermodynamic activities of the unionized and ionized species on drug flux across buccal mucosa. J Pharm Sci. 2008;97:4294–306.

    Article  CAS  Google Scholar 

  21. Mashru R, Sutariya V, Sankalia M, Sankalia J. Transbuccal delivery of lamotrigine across porcine buccal mucosa: in vitro determination of routes of buccal transport. J Pharm Pharm Sci. 2005;8:54–62.

    CAS  PubMed  Google Scholar 

  22. Ruifrok PG. Transport of organic ions through lipid bilayers. The barbiturates. Naunyn Schmiedeberg’s Arch Pharmacol. 1982;319:185–8.

    Article  CAS  Google Scholar 

  23. Thomae AV, Wunderli-Allenspach H, Krämer SD. Permeation of aromatic carboxylic acids across lipid bilayers: the pH-partition hypothesis revisited. Biophys J. 2005;89:1802–11.

    Article  CAS  Google Scholar 

  24. Dahlgren D, Lennernäs H. Intestinal permeability and drug absorption: predictive experimental, computational and in vivo approaches. Pharmaceutics. 2019;11:411.

    Article  CAS  Google Scholar 

  25. Lennernäs H. Intestinal permeability and its relevance for absorption and elimination. Xenobiotica. 2007;37:1015–51.

    Article  Google Scholar 

  26. Levitt DG. Quantitation of small intestinal permeability during normal human drug absorption. BMC Pharmacol Toxicol. 2013;14:34.

    Article  CAS  Google Scholar 

  27. Hollander D, Dadufalza VD, Fairchild PA. Intestinal absorption of aspirin. Influence of pH, taurocholate, ascorbate, and ethanol. J Lab Clin Med. 1981;98:591–8.

    CAS  PubMed  Google Scholar 

  28. Swietach P, Hulikova A, Patiar S, Vaughan-Jones RD, Harris AL. Importance of intracellular pH in determining the uptake and efficacy of the weakly basic chemotherapeutic drug, doxorubicin. PLoS One. 2012;7:e35949.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Bioactive Research and Development (LIDeB), Department of Biological Sciences, Faculty of Exact Sciences, University of La Plata (UNLP), La Plata, Argentina

    Alan Talevi & Carolina L. Bellera

  2. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina

    Alan Talevi & Carolina L. Bellera

Authors
  1. Alan Talevi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carolina L. Bellera
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alan Talevi .

Section Editor information

  1. Laboratory of Bioactive Research and Development (LIDeB), Department of Biological Sciences, Faculty of Exact Sciences, University of La Plata (UNLP), La Plata, Argentina

    Alan Talevi

  2. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina

    Alan Talevi

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Switzerland AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Talevi, A., Bellera, C.L. (2021). pH Partition Theory. In: The ADME Encyclopedia. Springer, Cham. https://doi.org/10.1007/978-3-030-51519-5_48-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-51519-5_48-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-51519-5

  • Online ISBN: 978-3-030-51519-5

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation