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

Álvarez-Figueroa, María Javiera; Pessoa‐Mahana, C. David; Palavecino-González, M. Elisa; Mella, Jaime; Espinosa‐Bustos, Christian; Lagos-Muñoz, Manuel E.

doi:10.1208/s12249-011-9622-1

Cited by 19 publications

(17 citation statements)

References 34 publications

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“…Compounds with Log P values between 1 and 4 have been shown to have ideal liphophilicity and aqueous solubility to penetrate biological membranes. Further, compounds with Log P greater than 4 have been predicted to have poor aqueous solubility and intestinal absorption [30]. Based on this theory, diosgenin is expected to have lower permeability than dioscin, which is in accordance to our observations.…”

supporting

confidence: 89%

Characterization of in Vitro ADME Properties of Diosgenin and Dioscin from Dioscorea villosa

et al. 2013

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Dioscorea villosa (wild yam) is native to North America and has been widely used as a natural alternative for estrogen replacement therapy to improve women’s health as well as to treat inflammation, muscle spasm, and asthma. Diosgenin and dioscin (glycoside form of diosgenin) are reported to be the pharmacologically active compounds. Despite the reports of significant pharmacological properties of dioscin and diosgenin in conditions related to inflammation, cancer, diabetes, and gastrointestinal ailments, no reports are available on ADME properties of these compounds. This study was carried out to determine ADME properties of diosgenin and dioscin and their effects on major drug metabolizing enzymes (CYP 3A4, 2D6, 2C9, and 1A2). The stability was determined in simulated gastric and intestinal fluids (SGF, pH 1.2 and SIF, pH 6.8), and intestinal transport was evaluated in Caco-2 model. Phase I and phase II metabolic stability was determined in human liver microsomes and S9 fractions, respectively. Quantitative analysis of dioscin and diosgenin was performed by UPLC-MS system. Dioscin degraded up to 28.3% in SGF and 12.4% in SIF, which could be accounted for by its conversion to diosgenin (24.2%. in SGF and 2.4% in SIF). The depletion of diosgenin in SGF and SIF was < 10%. Diosgenin was stable in HLM but disappeared in S9 fraction with a half-life of 11.3 min. In contrast, dioscin was stable in both HLM and S9 fractions. Dioscin showed higher permeability across Caco-2 monolayer with no significant efflux, while diosgenin was subjected to efflux mediated by P-glycoprotein. Diosgenin and dioscin inhibited CYP3A4 with IC50 values of 17 and 33 μM, respectively, while other CYP enzymes were not affected. In conclusion, dioscin showed better intestinal permeability. Conversion of dioscin to diosgenin was observed in both gastric and intestinal fluids. No phase I metabolism was detected for both compounds. The disappearance of diosgenin in S9 fraction indicated phase II metabolism.

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confidence: 89%

Characterization of in Vitro ADME Properties of Diosgenin and Dioscin from Dioscorea villosa

et al. 2013

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“…The parallel artificial membrane permeation assay (PAMPA) is a method by which the permeability of a substance through a lipid-infused artificial membrane can be determined [12] , [13] . Although there is no active transport in the PAMPA membrane, it is a useful model for predicting the transport behavior of highly lipophilic drug candidates by transcellular absorption.…”

Section: Introductionmentioning

confidence: 99%

Gintonin absorption in intestinal model systems

Lee

Choi

Kim

et al. 2018

Journal of Ginseng Research

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BackgroundRecently, we identified a novel ginseng-derived lysophosphatidic acid receptor ligand, called gintonin. We showed that gintonin induces [Ca2+]i transient-mediated morphological changes, proliferation, and migration in cells expressing lysophosphatidic acid receptors and that oral administration of gintonin exhibits anti-Alzheimer disease effects in model mice. However, little is known about the intestinal absorption of gintonin. The aim of this study was to investigate gintonin absorption using two model systems.MethodsGintonin membrane permeation was examined using a parallel artificial membrane permeation assay, and gintonin absorption was evaluated in a mouse everted intestinal sac model.ResultsThe parallel artificial membrane permeation assay showed that gintonin could permeate an artificial membrane in a dose-dependent manner. In the everted sac model, gintonin absorption increased with incubation time (from 0 min to 60 min), followed by a decrease in absorption. Gintonin absorption into everted sacs was also dose dependent, with a nonlinear correlation between gintonin absorption and concentration at 0.1–3 mg/mL and saturation at 3–5 mg/mL. Gintonin absorption was inhibited by the Rho kinase inhibitor Y-27632 and the sodium–glucose transporter inhibitor phloridzin. Moreover, lipid extraction with methanol also attenuated gintonin absorption, suggesting the importance of the lipid portion of gintonin in absorption. This result shows that gintonin might be absorbed through passive diffusion, paracellular, and active transport pathways.ConclusionThe present study shows that gintonin could be absorbed in the intestine through transcellular and paracellular diffusion, and active transport. In addition, the lipid component of gintonin might play a key role in its intestinal absorption.

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“…PAMPA was performed to estimate passive transcellular permeability. PAMPA is a non-cell-based permeability model, but it is considered robust, reproducible, or fast [34][35][36]. It was demonstrated that PAMPA can be used to predict the passive permeability through the gastrointestinal tract of constituents in a complex plant extract [37].…”

Section: Resultsmentioning

confidence: 99%

Enhanced Solubility and Permeability of Salicis cortex Extract by Formulating as a Microemulsion

et al. 2018

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A microemulsion system was developed and investigated as a novel oral formulation to increase the solubility and absorption of Salicis cortex extract. This extract possesses many pharmacological activities, in particular, it is beneficial for back pain and osteoarthritic and rheumatic complaints. In this work, after qualitative and quantitative characterization of the extract and the validation of an HPLC/diode array detector analytical method, solubility studies were performed to choose the best components for microemulsion formulation. The optimized microemulsion consisted of 2.5 g of triacetin, as the oil phase, 2.5 g of Tween 20 as the surfactant, 2.5 g of labrasol as the cosurfactant, and 5 g of water. The microemulsion was visually checked, characterized by light scattering techniques and morphological observations. The developed formulation appeared transparent, the droplet size was around 40 nm, and the -potential result was negative. The maximum loading content of Salicis cortex extract resulted in 40 mg/mL. Furthermore, storage stability studies and an digestion assay were performed. The advantages offered by microemulsion were evaluated using artificial membranes and cells, i.e., parallel artificial membrane permeability assay and a Caco-2 model. Both studies proved that the microemulsion was successful in enhancing the permeation of extract compounds, so it could be useful to ameliorate the bioefficacy of Salicis cortex.

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

Cited by 19 publications

References 34 publications

Characterization of in Vitro ADME Properties of Diosgenin and Dioscin from Dioscorea villosa

Characterization of in Vitro ADME Properties of Diosgenin and Dioscin from Dioscorea villosa

Gintonin absorption in intestinal model systems

Enhanced Solubility and Permeability of Salicis cortex Extract by Formulating as a Microemulsion

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