The Importance of Drug‐Membrane Interaction in Drug Research and Development

Seydel, Joachim K.; Velasco, M. Albores; Coats, Eugene A.; Cordes, H. P.; Kunz, B.; Wiese, Michael

doi:10.1002/qsar.19920110216

Cited by 44 publications

(22 citation statements)

References 7 publications

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“…Indeed good correlations have been found between NMR slopes and log D lip as well as other lipophilicity descriptors obtained using artificial membranes. 7,45,50 The NMR method can also afford information on the interaction of distinct molecular fragments with phospholipids, by comparing, within the same solute, the NMR slopes of different signals corresponding to distinct molecular fragments. In this case, since different molecular portions may interact differently with liposomes, the relationship between log D lip and the NMR slope is not univocal, but may vary according to the signal being monitored.…”

Section: Principle Of 1 H-nmr Studies To Obtain Relaxation Rates As Mmentioning

confidence: 99%

“…7 Such interactions can be classified according to the role played by membranes (Table I), and various experimental approaches have been proposed to simulate the above cases of drug-membrane interactions.…”

Section: B Partitioning or Binding?mentioning

confidence: 99%

“…6), can be used to quantify the degree of interaction of the molecule with liposomes, provided that no other factor can lead to signal broadening. 7,56 Within a structurally related series of compounds, the NMR slopes relative to an appropriate common spin system taken as a probe, can be considered a indirect measurement of log D lip . Indeed good correlations have been found between NMR slopes and log D lip as well as other lipophilicity descriptors obtained using artificial membranes.…”

Section: Principle Of 1 H-nmr Studies To Obtain Relaxation Rates As Mmentioning

confidence: 99%

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Liposome/water lipophilicity: Methods, information content, and pharmaceutical applications

Balen

Martinet

Caron

et al. 2004

Medicinal Research Reviews

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This review discusses liposome/water lipophilicity in terms of the structure of liposomes, experimental methods, and information content. In a first part, the structural properties of the hydrophobic core and polar surface of liposomes are examined in the light of potential interactions with solute molecules. Particular emphasis is placed on the physicochemical properties of polar headgroups of lipids in liposomes. A second part is dedicated to three useful methods to study liposome/water partitioning, namely potentiometry, equilibrium dialysis, and (1)H-NMR relaxation rates. In each case, the principle and limitations of the method are discussed. The next part presents the structural information encoded in liposome/water lipophilicity, in other words the solutes' structural and physicochemical properties that determine their behavior and hence their partitioning in such systems. This presentation is based on a comparison between isotropic (i.e., solvent/water) and anisotropic (e.g., liposome/water) systems. An important factor to be considered is whether the anisotropic lipid phase is ionized or not. Three examples taken from the authors' laboratories are discussed to illustrate the factors or combinations thereof that govern liposome/water lipophilicity, namely (a) hydrophobic interactions alone, (b) hydrophobic and polar interactions, and (c) conformational effects plus hydrophobic and ionic interactions. The next part presents two studies taken from the field of QSAR to exemplify the use of liposome/water lipophilicity in structure-disposition and structure-activity relationships. In the conclusion, we summarize the interests and limitations of this technology and point to promising developments.

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Section: Principle Of 1 H-nmr Studies To Obtain Relaxation Rates As Mmentioning

confidence: 99%

Section: B Partitioning or Binding?mentioning

confidence: 99%

Section: Principle Of 1 H-nmr Studies To Obtain Relaxation Rates As Mmentioning

confidence: 99%

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Liposome/water lipophilicity: Methods, information content, and pharmaceutical applications

Balen

Martinet

Caron

et al. 2004

Medicinal Research Reviews

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“…Recently, therefore, other model partition systems have been investigated (for a survey of systems, techniques and results see Seydel [3,4]). It has been pointed out that the partition parameters derived from liposome-water systems outperform the octanol-water system for the prediction of biological activities of certain classes of drugs [5].…”

Section: Introductionmentioning

confidence: 99%

pH-Dependent Partitioning of Acidic and Basic Drugs into Liposomes—A Quantitative Structure-Activity Relationship Analysis

Schaper¹,

Zhang

Raevsky

2001

Quant. Struct.-Act. Relat.

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The partitioning of drugs in the phospholipid liposomeywater system has often been used as a model for the investigation of drugycell membrane interactions. Generally distributiony pH pro®les for acidic and basic compounds observed in the phospholipidywater system cannot be predicted by pro®les obtained in the octanolywater system. This is true especially for pH regions where acids and bases are ionized. Based on the well-known pH-partition theory our nonlinear regression analysis of published pH-dependent liposome-water distribution coef®cients of 18 basic and acidic drugs resulted in equations with satisfactory predictive power. Surprisingly the separate equations describing the partitioning of neutral, anionic or cationic drugs into phosphatidylcholine liposomes are rather similar with respect to signi®cant physicochemical properties and their regression coef®cients. Despite being differently charged the distribution of all three species into the phospholipid bilayer increases with sizeybulk (polarizability a) and decreases with polarity characterized by the sum of substructural partial charges. Furthermore, for the neutral compounds and their cations an unfavorable effect of H-bond acceptor strength on distribution is found. Unexpectedly the H-bond donor effect of neutral or ionized species does not seem to in¯uence their liposome partitioning behavior (as observed within each group of neutral, cationic or anionic drugs). Generally the distribution of ionizable molecules into phospholipid bilayers decreases with increasing degree of ionization. In this data set it was found for the ®rst time that speci®c NÀH-acidic drugs may show the opposite behavior. Obviously anions with a delocalized negative charge like anions of tautomeric pyrimidinonesypyrimidinols have the possibility to enter into some strong special interaction with phospholipid molecules.

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“…Значај мембрана за деловање лека показао је и Зајдел (Seydel) [73,74]. Мембрана може да утиче на молекуле лекова на следеће начине:…”

Section: слика 17unclassified

Investigation of structural effects on the anticonvulsant activity of 3,5-disubstituted-5-phenylhydantoins by the linear solvation relationship method

Trišović¹

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The Importance of Drug‐Membrane Interaction in Drug Research and Development

Cited by 44 publications

References 7 publications

Liposome/water lipophilicity: Methods, information content, and pharmaceutical applications

Liposome/water lipophilicity: Methods, information content, and pharmaceutical applications

pH-Dependent Partitioning of Acidic and Basic Drugs into Liposomes—A Quantitative Structure-Activity Relationship Analysis

Investigation of structural effects on the anticonvulsant activity of 3,5-disubstituted-5-phenylhydantoins by the linear solvation relationship method

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