PAMPA—critical factors for better predictions of absorption

Avdeef, Alex; Bendels, Stefanie; Di, Li; Faller, Bernard; Kansy, Manfred; Sugano, Kiyohiko; Yamauchi, Yukiko

doi:10.1002/jps.21068

Cited by 217 publications

(162 citation statements)

References 50 publications

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“…The PAMPA method was employed, as described previously. 10,[49][50][51][52][53][54] Peptides were prepared at a concentration of 180 µM for NATA and ∼600 µM for NAYA and NAFA. All samples were prepared in both 20 mM sodium acetate buffer at pH 4.8 and 20 mM sodium phosphate buffer at pH 7.2.…”

Section: Methodsmentioning

confidence: 99%

Permeation of the three aromatic dipeptides through lipid bilayers: Experimental and computational study

Lee

Kuczera

Middaugh

et al. 2016

The Journal of Chemical Physics

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The time-resolved parallel artificial membrane permeability assay with fluorescence detection and comprehensive computer simulations are used to study the passive permeation of three aromatic dipeptides—N-acetyl-phenylalanineamide (NAFA), N-acetyltyrosineamide (NAYA), and N-acetyl-tryptophanamide (NATA) through a 1,2-dioleoyl-sn-glycero-3-phospocholine (DOPC) lipid bilayer. Measured permeation times and permeability coefficients show fastest translocation for NAFA, slowest for NAYA, and intermediate for NATA under physiological temperature and pH. Computationally, we perform umbrella sampling simulations to model the structure, dynamics, and interactions of the peptides as a function of z, the distance from lipid bilayer. The calculated profiles of the potential of mean force show two strong effects—preferential binding of each of the three peptides to the lipid interface and large free energy barriers in the membrane center. We use several approaches to calculate the position-dependent translational diffusion coefficients D(z), including one based on numerical solution the Smoluchowski equation. Surprisingly, computed D(z) values change very little with reaction coordinate and are also quite similar for the three peptides studied. In contrast, calculated values of sidechain rotational correlation times τrot(z) show extremely large changes with peptide membrane insertion—values become 100 times larger in the headgroup region and 10 times larger at interface and in membrane center, relative to solution. The peptides’ conformational freedom becomes systematically more restricted as they enter the membrane, sampling α and β and C7eq basins in solution, α and C7eq at the interface, and C7eq only in the center. Residual waters of solvation remain around the peptides even in the membrane center. Overall, our study provides an improved microscopic understanding of passive peptide permeation through membranes, especially on the sensitivity of rotational diffusion to position relative to the bilayer.

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Section: Methodsmentioning

confidence: 99%

Permeation of the three aromatic dipeptides through lipid bilayers: Experimental and computational study

Lee

Kuczera

Middaugh

et al. 2016

The Journal of Chemical Physics

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“…Particular attention has been paid to the ability of the fumarate salt of donecopride (chosen among a series of salts) to cross the BBB. According to a parallel artificial membrane permeability assay experiment (38), the drug (M r = 508 g·mol −1 ) was classified among the compounds as having good brain penetration with logPe = −4.43 ± 0.10 (Pe represents the PAMPA effective permeability coefficient). This result was fully confirmed after performing a cellular test using bovine brain capillary endothelial cells and rat glial cells with Pe > 2 × 10 −3 cm/min (Fig.…”

Section: Donecopride Promotes the Sappα Secretion In An In Vitro Cellmentioning

confidence: 99%

Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment

Lecoutey

Hédou

Freret

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

103

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RS67333 is a partial serotonin subtype 4 receptor (5-HT 4 R) agonist that has been widely studied for its procognitive effect. More recently, it has been shown that its ability to promote the nonamyloidogenic cleavage of the precursor of the neurotoxic amyloid-β peptide leads to the secretion of the neurotrophic protein sAPPα. This effect has generated great interest in RS67333 as a potential treatment for Alzheimer's disease (AD). We show herein that RS67333 is also a submicromolar acetylcholinesterase (AChE) inhibitor and therefore, could contribute, through this effect, to the restoration of the cholinergic neurotransmission that becomes altered in AD. We planned to pharmacomodulate RS67333 to enhance its AChE inhibitory activity to take advantage of this pleiotropic pharmacological profile in the design of a novel multitargetdirected ligand that is able to exert not only a symptomatic but also, a disease-modifying effect against AD. These efforts allowed us to select donecopride as a valuable dual (h)5-HT 4 R partial agonist (K i = 10.4 nM; 48.3% of control agonist response)/(h)AChEI (IC 50 = 16 nM) that further promotes sAPPα release (EC 50 = 11.3 nM). Donecopride, as a druggable lead, was assessed for its in vivo procognitive effects (0.1, 0.3, 1, and 3 mg/kg) with an improvement of memory performances observed at 0.3 and 1 mg/kg on the object recognition test. On the basis of these in vitro and in vivo activities, donecopride seems to be a promising drug candidate for AD treatment.

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“…The extent of permeation through the membrane is measured and compared with a known degree of drug absorption in humans. An excellent correlation was demonstrated between the flux across PAMPA systems and the extent of absorption of a diverse set of well-characterized drugs in humans (16)(17)(18)(19)(20)(21). No good correlation is observed when the drug is transported by active transport mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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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PAMPA—critical factors for better predictions of absorption

Cited by 217 publications

References 50 publications

Permeation of the three aromatic dipeptides through lipid bilayers: Experimental and computational study

Permeation of the three aromatic dipeptides through lipid bilayers: Experimental and computational study

Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment

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

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