Ionization and Partitioning Profiles of Zwitterions: The case of the anti‐inflammatory drug azapropazone

Caron, Giulia; Pagliara, Alessandra; Gaillard, Patrick; Carrupt, Pierre‐Alain; Testa, Bernard

doi:10.1002/hlca.19960790618

Cited by 21 publications

(10 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…pounds such as nigericin, [22] azapropazone, [23] piroxicam, [24] chloroquine [25] or tenidap [26,27] are able to correct for these dysfunctions. The representation of the data as an ionic partition diagram allows us to understand how ionisable compounds can facilitate the transfer of protons from an aqueous phase to another medium (such as a cellular membrane) and affords a useful way to interpret the behaviour of pH-modulating agents in biological environments.…”

Section: Resultsmentioning

confidence: 99%

Charge and Delocalisation Effects on the Lipophilicity of Protonable Drugs

et al. 1999

Self Cite

View full text Add to dashboard Cite

The transfer mechanisms of ionisable compounds of pharmaceutical interest were studied by cyclic voltammetry at the water/1,2-dichloroethane interface. The partition coefficients of the various ions were deduced from the voltammograms which were monitored as a function of aqueous pH. The dissociation constants and the partition coefficients of the neutral species were determined by a pH-metric titration technique, and the results obtained are displayed in the form of ionic partition diagrams which define the predomi-nance domains of each species in both phases. These diagrams afford an easy interpretation of the mechanisms governing ion transfer and show how neutral species can facilitate the passage of protons from water into an organic phase and thus how ionisable compounds can modulate the pH. The change in lipophilicity between charged and neutral forms of a given compound is discussed in terms of an intramolecular stabilisation of the charge. The nature of the substituents surrounding the charged atom as well as the degree of delocalisation of the charge are shown to contribute markedly to the stabilisation of ionic species in the organic phase. Borns solvation model is also used to illustrate qualitatively the effect of the molecular radius on the lipophilicity and to show that ions retain more water molecules when they transfer into octanol than into 1,2-dichloroethane.

show abstract

Section: Resultsmentioning

confidence: 99%

Charge and Delocalisation Effects on the Lipophilicity of Protonable Drugs

et al. 1999

Self Cite

View full text Add to dashboard Cite

show abstract

“…The parameter diff(log P N−I ) is also of interest in the study of zwitterions, which are receving much interest due to their peculiar partitioning and pharmacokinetic behavior (53)(54)(55). The pH-partitioning profiles of ampholites (56) can be bell-shaped or U-shaped.…”

Section: The Diff(log P N−i ) Parametersmentioning

confidence: 99%

Lipophilicity and Its Relationship with Passive Drug Permeation

2010

Self Cite

View full text Add to dashboard Cite

In this review, we first summarize the structure and properties of biological membranes and the routes of passive drug transfer through physiological barriers. Lipophilicity is then introduced in terms of the intermolecular interactions it encodes. Finally, lipophilicity indices from isotropic solvent systems and from anisotropic membrane-like systems are discussed for their capacity to predict passive drug permeation across biological membranes such as the intestinal epithelium, the blood-brain barrier (BBB) or the skin. The broad evidence presented here shows that beyond the predictive power of lipophilicity parameters, the various intermolecular forces they encode allow a mechanistic interpretation of passive drug permeation.

show abstract

“…A variety of experimental and computational methods were used to examine the multiple protonation/deprotonation equilibria, tautomerism, and pH-lipophilicity profiles of the nonsteroidal antiinflammatory drug azapropazone (11). 50 This zwitterionic compound demonstrated a large value of K Z (∆pK a > 5), and here again a broad plateau between the two pK a was obtained in octanol/ water and dodecane/water. Unfortunately, the region below the acidic pK a is not experimentally accessible, thus hiding the full bell shape of these curves.…”

Section: Zwitterions With a Large K Zmentioning

confidence: 99%

“…c. Charge Delocalization Operating through One or More π -Bonds. A variety of experimental and computational methods were used to examine the multiple protonation/deprotonation equilibria, tautomerism, and pH-lipophilicity profiles of the nonsteroidal antiinflammatory drug azapropazone ( 11 ) This zwitterionic compound demonstrated a large value of K Z (Δp K a > 5), and here again a broad plateau between the two p K a was obtained in octanol/water and dodecane/water.…”

Section: Zwitterions With a Large K Zmentioning

confidence: 99%

Lipophilicity Profiles of Ampholytes

et al. 1997

Self Cite

View full text Add to dashboard Cite

ContentsI. Introduction 3385 A. Significance of Amphoteric Drugs and Biomolecules 3385 B. Partitioning of Amphoteric Drugs: Zwitterions Compared to Ordinary Ampholytes 3386 II. Theoretical Background 3386 A. Acid−Base Equilibria 3386 1. Ordinary Ampholytes 3386 2. Zwitterionic Ampholytes: Microdissociation Equilibria and Micro-pK a 3387 3. Zwitterionic Ampholytes Having a Large Value of K Z 3388 B. Partitioning of Zwitterions 3389 1. General Assumptions for Ionizable Solutes 3389 2. General Assumptions for Zwitterionic Ampholytes 3389 3. Zwitterions Having a Large Value of K Z 3391 III. Relevant Techniques 3391 A. Experimental Techniques 3391 1. Measurements of pK a Values 3391 2. Investigation of Microdissociation Equilibria: Assignment of Micro-pK a and K Z 3391 3. Measurement of Lipophilicity Profiles 3392 B. Computational Techniques 3392 1. Two-Dimensional Fragmental Systems 3392 2. Calculation of Virtual log P Values 3392 IV. Lipophilicity Profiles of Zwitterionic Ampholytes 3392 A. Bell-Shaped Distribution Profiles 3392 1. Zwitterions with a Small K Z 3392 2. Zwitterions with a Large K Z 3394 B. U-Shaped Distribution Profiles 3396 C. Counterion Effects on the Partitioning of Cations and Anions 3397 V. Conclusions 3397 A. Physicochemical Outlook 3397 B. Pharmacokinetic Relevance 3397 VI. Acknowledgments 3398 VII. Glossary 3398 VIII. References 3399

show abstract

Ionization and Partitioning Profiles of Zwitterions: The case of the anti‐inflammatory drug azapropazone

Cited by 21 publications

References 26 publications

Charge and Delocalisation Effects on the Lipophilicity of Protonable Drugs

Charge and Delocalisation Effects on the Lipophilicity of Protonable Drugs

Lipophilicity and Its Relationship with Passive Drug Permeation

Lipophilicity Profiles of Ampholytes

Contact Info

Product

Resources

About