Comparing the Lipid Membrane Affinity and Permeation of Drug-like Acids: The Intriguing Effects of Cholesterol and Charged Lipids

Thomae, Anita V.; Koch, Tamara; Panse, Christian; Wunderli‐Allenspach, Heidi; Krämer, Stefanie-Dorothea

doi:10.1007/s11095-007-9263-y

Cited by 53 publications

(77 citation statements)

References 39 publications

(58 reference statements)

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“…(1)] of small substances. [38] Planar bilayers also allowed direct determination of P M,SA− with 4×10 −7 cm s −1 [6] from transmembrane current measurements carried out under voltage clamp conditions. That is, if properly measured, both the absolute value of P M,SA and the difference between P M,SA− and P M,SA agree well with what has been predicted by the Meyer-Overton rule.…”

Section: Aromatic Weak Acidsmentioning

confidence: 99%

110 Years of the Meyer–Overton Rule: Predicting Membrane Permeability of Gases and Other Small Compounds

2009

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The transport of gaseous compounds across biological membranes is essential in all forms of life. Although it was generally accepted that gases freely penetrate the lipid matrix of biological membranes, a number of studies challenged this doctrine as they found biological membranes to have extremely low gas-permeability values. These observations led to the identification of several membrane-embedded "gas" channels, which facilitate the transport of biological active gases, such as carbon dioxide, nitric oxide, and ammonia. However, some of these findings are in contrast to the well-established solubility-diffusion model (also known as the Meyer-Overton rule), which predicts membrane permeabilities from the molecule's oil-water partition coefficient. Herein, we discuss recently reported violations of the Meyer-Overton rule for small molecules, including carboxylic acids and gases, and show that Meyer and Overton continue to rule.

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Section: Aromatic Weak Acidsmentioning

confidence: 99%

110 Years of the Meyer–Overton Rule: Predicting Membrane Permeability of Gases and Other Small Compounds

2009

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“…Kinetic Models to Describe Lipid-Bilayer Permeation. -Two models to describe the kinetics of lipid-bilayer permeation will be discussed: a diffusion model following Ficks first law and a flip-flop model, which is based on a three-step mechanism, namely partitioning into one lipid layer, translocation (flip-flop) to the opposite lipid layer, and partitioning out of the opposite lipid layer [2] [3]. Following the diffusion model, no significant permeation of charged compounds across lipid bilayers is expected.…”

Section: Characteristics Of Lipidmentioning

confidence: 99%

“…Only in a few cases, they were mono-exponential [3] [4] [5]. To account for this and to accurately describe our permeation kinetics and to shed light on the permeation mechanisms, we use the flipflop model described in the next section rather than the diffusion model to interpret the data of our liposomal permeation assay and to analyze drug -membrane interactions by surface plasmon resonance technology [6].…”

Section: Characteristics Of Lipidmentioning

confidence: 99%

“…Another significant difference between isotropic partition phases such as octan-1-ol or alkanes, and lipid bilayers is the relatively high affinity of charged compounds to the latter [3] [10 -15]. This is attributed to electrostatic interactions, including chargecharge interactions, between these compounds and the lipid head groups.…”

Section: Characteristics Of Lipidmentioning

confidence: 99%

“…Based on the above model, lipid-bilayer permeation of amphiphilic drugs can be divided into three major steps: i) the partitioning of the solute from an aqueous phase into the respective lipid leaflet of the bilayer, ii) the translocation of the solute between the two lipid leaflets, also called flip-flop, and iii) the partitioning of the solute out of the lipid leaflet into the opposite aqueous phase [2] [3]. In the case of a weak monoprotic acid or base, the solute can in addition change its protonation state in the aqueous phases and in the lipid leaflets.…”

Section: Characteristics Of Lipidmentioning

confidence: 99%

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Lipid‐Bilayer Permeation of Drug‐Like Compounds

Krämer

Lombardi

Primorac

et al. 2009

Chemistry & Biodiversity

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Lipid-bilayer permeation is determinant for the disposition of xenobiotics in the body. It controls the pharmacokinetic behavior of drugs and is, in many cases, a prerequisite for intracellular targeting. Permeation of in vivo barriers is in general predicted from lipophilicity and related parameters. This article goes beyond the empirical correlations, and elucidates the processes and their interplay determining bilayer permeation. A flip-flop model for bilayer permeation, which considers the partitioning rate constants beside the translocation rate constants, is compared with the diffusion model based on Fick's first law. According to the flip-flop model, the ratios of aqueous volumes to barrier area can determine whether partitioning or translocation is rate-limiting. The flip-flop model allows permeation of anions and cations, and expands our understanding of pH-dependent permeation kinetics. Some experimental evidences for ion-controlled permeation at pH 7 are also included in this work.

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Moment theory for the analytical determination of rate constants for solute permeation at the interface of spherical molecular aggregates

2019

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Moment equations were developed on the basis of the Einstein equation for diffusion and the random walk model to analytically determine the rate constant for the interfacial solute permeation from a bulk solvent into molecular aggregates (kin) and the inverse rate constant from the molecular aggregates to the bulk solvent (kout). The moment equations were in good agreement with those derived in a different manner. To demonstrate their effectiveness in one concrete example, the moment equations were used to analytically determine the values of kin and kout of three electrically neutral solutes, i.e. resorcinol, phenol, and nitrobenzene, from the first absolute (μ1A) and second central (μ2C) moments of their elution peaks, as measured by electrokinetic chromatography (EKC), in which the sodium dodecyl sulfate (SDS) micelles were used as a pseudostationary phase. The values of kin and kout should be determined with no chemical modifications and no physical action with the molecular aggregates because they are dynamic systems formed through weak interactions between the components. The moment analysis of the elution peak profiles measured by EKC is effective to unambiguously determine kin, kout, and the partition equilibrium constant (kin/kout) under appropriate experimental conditions.

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Comparing the Lipid Membrane Affinity and Permeation of Drug-like Acids: The Intriguing Effects of Cholesterol and Charged Lipids

Abstract: Depending on the single rate constants and on the geometry of the system, lipid bilayer permeation may positively, negatively or not correlate with the bilayer affinity of the permeant.

Cited by 53 publications

References 39 publications

110 Years of the Meyer–Overton Rule: Predicting Membrane Permeability of Gases and Other Small Compounds

110 Years of the Meyer–Overton Rule: Predicting Membrane Permeability of Gases and Other Small Compounds

Lipid‐Bilayer Permeation of Drug‐Like Compounds

Moment theory for the analytical determination of rate constants for solute permeation at the interface of spherical molecular aggregates

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