Permeation of permanently positive charged molecules through artificial membranes—Influence of physico-chemical properties

Fischer, Holger; Kansy, Manfred; Avdeef, Alex; Senner, Frank

doi:10.1016/j.ejps.2007.02.001

Cited by 74 publications

(86 citation statements)

References 25 publications

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“…However, both present a Pe>1 (10 −6 cm/s) (30). That is to say, the Log P oct values as well as the Pe values classify them as very permeable drugs, such that it is expected that if they were administered orally they would have an absorption >50%.…”

Section: Gastrointestinal Permeability Studies (Pampa)mentioning

confidence: 98%

Evaluation of the Membrane Permeability (PAMPA and Skin) of Benzimidazoles with Potential Cannabinoid Activity and their Relation with the Biopharmaceutics Classification System (BCS)

et al. 2011

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Abstract. The permeability of five benzimidazole derivates with potential cannabinoid activity was determined in two models of membranes, parallel artificial membrane permeability assay (PAMPA) and skin, in order to study the relationship of the physicochemical properties of the molecules and characteristics of the membranes with the permeability defined by the Biopharmaceutics Classification System. It was established that the PAMPA intestinal absorption method is a good predictor for classifying these molecules as very permeable, independent of their thermodynamic solubility, if and only if these have a Log P oct value <3.0. In contrast, transdermal permeability is conditioned on the solubility of the molecule so that it can only serve as a model for classifying the permeability of molecules that possess high solubility (class I: high solubility, high permeability; class III: high solubility, low permeability).

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Section: Gastrointestinal Permeability Studies (Pampa)mentioning

confidence: 98%

Evaluation of the Membrane Permeability (PAMPA and Skin) of Benzimidazoles with Potential Cannabinoid Activity and their Relation with the Biopharmaceutics Classification System (BCS)

et al. 2011

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“…All measurements were done in triplicate. Effective permeability values (Pe) were calculated as described previously (Avdeef et al, 2001;Fischer et al, 2007). PAMPA Evolution Software (version 3.3; pION Inc., Woburn, MA) was used for all Pe calculations.…”

mentioning

confidence: 99%

Design, Data Analysis, and Simulation of in Vitro Drug Transport Kinetic Experiments Using a Mechanistic in Vitro Model

Poirier

Lavé²,

Portmann³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The use of in vitro data for quantitative predictions of transportermediated elimination in vivo requires an accurate estimation of the transporter Michaelis-Menten parameters, V max and K m , as a first step. Therefore, the experimental conditions of in vitro studies used to assess hepatic uptake transport were optimized regarding active transport processes, nonspecific binding, and passive diffusion (P dif ). A mechanistic model was developed to analyze and accurately describe these active and passive processes. This twocompartmental model was parameterized to account for nonspecific binding, bidirectional passive diffusion, and active uptake processes based on the physiology of the cells. The model was used to estimate kinetic parameters of in vitro transport data from organic anion-transporting peptide model substrates (e.g., cholecystokinin octapeptide deltorphin II, fexofenadine, and pitavastatin). Data analysis by this mechanistic model significantly improved the accuracy and precision in all derived parameters [mean coefficient of variations (CVs) for V max and K m were 19 and 23%, respectively] compared with the conventional kinetic method of transport data analysis (mean CVs were 58 and 115%, respectively, using this method). Furthermore, permeability was found to be highly temperature-dependent in Chinese hamster ovary (CHO) control cells and artificial membranes (parallel artificial membrane permeability assay). Whereas for some compounds (taurocholate, estrone-3-sulfate, and propranolol) the effect was moderate (1.5-6-fold higher permeability at 37°C compared with that at 4°C), for fexofenadine a 16-fold higher passive permeability was seen at 37°C. Therefore, P dif was better predicted if it was evaluated under the same experimental conditions as V max and K m , i.e., in a single incubation of CHO overexpressed cells or rat hepatocytes at 37°C, instead of a parallel control evaluation at 4°C.

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“…There are several experimental studies supporting this assumption, which is called the pH -partition hypothesis [23 -25] [27]. The permeation of quaternary amines through lipid-impregnated filters [28] strongly supports the hypothesis that ions can efficiently permeate lipid bilayers.…”

Section: Characteristics Of Lipidmentioning

confidence: 87%

“…With this complexity in mind, it is advisable to continue with estimating permeation and permeation-related ADME processes from correlation-derived, structure-based descriptors [52 -55] or physicochemical parameters [29] [56] [57], or from transport studies across artificial barriers [28] [58] or cell layers [59] [60]. However, more advanced experiments on lipid-bilayer permeation taking into account all of the above considerations should provide valuable information for a better understanding of passive and transporter-activated barrier passage and finally an improvement of the models.…”

Section: Conclusion and Extrapolation To The In Vivomentioning

confidence: 99%

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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Permeation of permanently positive charged molecules through artificial membranes—Influence of physico-chemical properties

Cited by 74 publications

References 25 publications

Evaluation of the Membrane Permeability (PAMPA and Skin) of Benzimidazoles with Potential Cannabinoid Activity and their Relation with the Biopharmaceutics Classification System (BCS)

Evaluation of the Membrane Permeability (PAMPA and Skin) of Benzimidazoles with Potential Cannabinoid Activity and their Relation with the Biopharmaceutics Classification System (BCS)

Design, Data Analysis, and Simulation of in Vitro Drug Transport Kinetic Experiments Using a Mechanistic in Vitro Model

Lipid‐Bilayer Permeation of Drug‐Like Compounds

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