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Selection Considerations for Membranes and Models for In Vitro/Ex Vivo Permeation Studies
Published in Tapash K. Ghosh, Dermal Drug Delivery, 2020
Pei-Chin Tsai, Tannaz Ramezanli, Dina W. Ameen, Sonia Trehan, Nathaly Martos, Zheng Zhang, Bozena Michniak-Kohn
Parallel artificial membrane permeability assay (PAMPA) was first introduced by Kansy et al.79 to assist the rapid determination of the passive membrane permeability of drugs. In the PAMPA model, a multi-well microtiter plate is used for the donor compartment and the receptor compartment is located on the top separated by a lipid-infused artificial membrane. To date, the PAMPA models have been correlated with drug permeation across a variety of barriers including gastrointestinal tract80, blood brain barrier81 and skin.82 This method has drawn attention in the pharmaceutical industry for screening lead candidates during early-discovery phase based on the low cost and high-throughput. Ottaviani et al.82 developed a skin-specific model, Skin-PAMPA, which incorporated different ratios of silicon oil and isopropyl myristate mixtures on polyvinylidene fluoride (PVDF) membranes. A correlation of permeability coefficients was reported between the Skin-PAMAPA model (70% silicon and 30% isopropyl myristate) and human skin for 19 compounds. In addition, the retention values of tested compounds on the Skin-PAMAPA model were correlated to the stratum corneum/water partition coefficient, which suggests that the model could reflect the affinity of compounds to the stratum corneum barrier.
Alteration of Intestinal Function by Xenobiotic Exposure
Published in Shayne C. Gad, Toxicology of the Gastrointestinal Tract, 2018
The Parallel Artificial Membrane Permeability Assay (PAMPA) was first introduced in 1998 (Kansy et al., 1998) and since then numerous reports have been published illustrating the general applicability of this model as a high throughput permeability screening tool (Joffe, 1971; Jilge, 1982; Spidogel et al., 2011; Jacobson, 2017). The model consists of a hydrophobic filter material coated with a mixture of lecithin/phospholipids dissolved in an inert organic solvent such as dodecane creating an artificial lipid membrane barrier that mimics the intestinal epithelium. The rate of permeation across the membrane barrier was shown to correlate well with the extent of drug absorption in humans. The use of 96-well microtiter plates coupled with rapid analysis using a spectrophotometric plate reader makes this system a very attractive model for screening a large number of compounds and libraries. PAMPA is much less labor intensive than cell culture methods, but it appears to show similar predictability. One of the main limitations of this model is that PAMPA underestimates the absorption of compounds that are actively absorbed via drug transporters. Despite the limitation, PAMPA may serve as an invaluable primary permeability screen during early drug discovery process because of its high throughput capability.
Morpholine-based chalcones as dual-acting monoamine oxidase-B and acetylcholinesterase inhibitors: synthesis and biochemical investigations
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Rani Sasidharan, Bo Hyun Eom, Jeong Hyun Heo, Jong Eun Park, Mohamed A. Abdelgawad, Arafa Musa, Nicola Gambacorta, Orazio Nicolotti, Sreedharannair Leelabaiamma Manju, Bijo Mathew, Hoon Kim
The synthesised derivatives were screened for their abilities to cross the BBB using the parallel artificial membrane permeability assay (PAMPA) because this ability is a critical developmental requirement for any drug targeting neurodegenerative disorders or depression. The PAMPA used was validated by comparing the experimentally determined permeabilities of eight commercial drugs with reported values (Table 2). According to reported BBB permeation limits, compounds were classified as follows:36 CNS+ (high): Pe (10−6 cm s−1) > 4.00, CNS- (low): Pe (10−6 cm s−1) <2.00 and CNS± (uncertain): Pe (10−6 cm s−1) from 4.00 to 2.00. Our results suggest that all nine synthesised derivatives could cross the BBB, and that MO1, MO5 and MO9 would be the most effective.
1-(Benzo[d]thiazol-2-yl)-3-phenylureas as dual inhibitors of casein kinase 1 and ABAD enzymes for treatment of neurodegenerative disorders
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Ondrej Benek, Lukas Hroch, Laura Aitken, Frank Gunn-Moore, Lucie Vinklarova, Kamil Kuca, Daniel I. Perez, Concepcion Perez, Ana Martinez, Zdenek Fisar, Kamil Musilek
Parallel Artificial Membrane Permeability Assay (PAMPA) is technique developed to predict passive permeability through biological membranes. In order to further explore the capacity of compounds K690 and K691 to penetrate into the brain, we used the PAMPA–BBB method described by Di et al.12, which employed a brain lipid porcine membrane. The in vitro permeability (Pe) of commercial drugs through lipid membrane extract together with compounds K690 and K691 were determined and described in Table 3. An assay validation was made comparing the reported permeability values of commercial drugs with the experimental data obtained employing this methodology. A good correlation between experimental-described values was obtained Pe (exptl) = 0.79 (bibl) – 0.4064 (R2 = 0.977) (Figure 3). From this equation and following the pattern established in the literature for BBB permeation prediction17 we could classify compounds as CNS + when they present a permeability >2.75 × 10−6 cm s−1. Based on these results we can consider that compounds K690 and K691 are able to cross the BBB by passive permeation (Table 3), although their calculated physical chemical properties do not fully meet the criteria suggested by CNS-MPO model (Table 2).
Preparation of curcumin self-micelle solid dispersion with enhanced bioavailability and cytotoxic activity by mechanochemistry
Published in Drug Delivery, 2018
Qihong Zhang, Nikolay E. Polyakov, Yulia S. Chistyachenko, Mikhail V. Khvostov, Tatjana S. Frolova, Tatjana G. Tolstikova, Alexandr V. Dushkin, Weike Su
The PAMPA enabled fast determination of the trends in the ability of the compounds to permeate membrane by passive diffusion and was thus suitable for screening potential drugs. Results (Figure 3(d)) showed a strong increasing of the amount of Cur permeated in comparison with a saturated aqueous solution of pure Cur used as control. In the case of Cur SD with the molar ratio of 1/1, 1/2, and 1/4, permeation could reach 7.05 μg, 9.46 μg, and 9.70 μg, respectively, during 3.5 h, suggesting higher ratio of Na2GA in SDs could promote Cur to faster membrane permeation. According to our previous NMR and molecular dynamics studies (Selyutina et al., 2016a,b), glycyrrhizin molecules are able to penetrate into lipid membranes and change their physical and functional properties, including permeability. The obtained results suggest a sharp increase in bioavailability of Cur from obtained Cur SD during experiments in vivo.