Abstract
BackgroundN-alkylamides (NAAs) are a large group of secondary metabolites occurring in more than 25 plant families which are often used in traditional medicine. A prominent active NAA is spilanthol. The general goal was to quantitatively investigate the gut mucosa and blood-brain barrier (BBB) permeability pharmacokinetic properties of spilanthol.MethodsSpilanthes acmella (L.) L. extracts, as well as purified spilanthol were used to investigate (1) the permeation of spilanthol through a Caco-2 cell monolayer in vitro, (2) the absorption from the intestinal lumen after oral administration to rats, and (3) the permeation through the BBB in mice after intravenous injection. Quantification of spilanthol was performed using a validated bio-analytical UPLC-MS2 method.ResultsSpilanthol was able to cross the Caco-2 cell monolayer in vitro from the apical-to-basolateral side and from the basolateral-to-apical side with apparent permeability coefficients Papp between 5.2 · 10−5 and 10.2 · 10−5 cm/h. This in vitro permeability was confirmed by the in vivo intestinal absorption in rats after oral administration, where an elimination rate constant ke of 0.6 h−1 was obtained. Furthermore, once present in the systemic circulation, spilanthol rapidly penetrated the blood-brain barrier: a highly significant influx of spilanthol into the brains was observed with a unidirectional influx rate constant K1 of 796 μl/(g · min).ConclusionsSpilanthol shows a high intestinal absorption from the gut into the systemic circulation, as well as a high BBB permeation rate from the blood into the brain.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-016-1159-0) contains supplementary material, which is available to authorized users.
Highlights
N-alkylamides (NAAs) are a large group of secondary metabolites occurring in more than 25 plant families which are often used in traditional medicine
Vitamin E-TPGS, Hanks’ Balanced Salt Solution (HBSS), trypan blue, potassium chloride (KCl), dimethylsulfoxide (DMSO), phosphate buffered saline (PBS), sodium chloride (NaCl), calcium chloride dehydrate (CaCl2.2H2O), sodium lactate, dichloromethane, sodium hydrogen carbonate (NaHCO3), sodium sulphate (Na2SO4), sodium dihydrogen phosphate (NaH2PO4), hydrochloric acid (HCl) and urethane were purchased from Sigma-Aldrich (Diegem, Belgium), while bovine serum albumin (BSA), disodium hydrogen phosphate dehydrate (Na2HPO4.2H2O), sodium dihydrogen phosphate monohydrate (NaH2PO4.H2O), sodium hydrogen carbonate and absolute ethanol (≥99.9 % V/V) were obtained from Merck KGaA (Darmstadt, Germany)
Caco-2 cell permeability Propranolol was used as a positive control and a apparent permeability coefficient (Papp),ab value of 19.1 · 10−6 cm/s was obtained, which is in good agreement with the values reported in literature [31]
Summary
N-alkylamides (NAAs) are a large group of secondary metabolites occurring in more than 25 plant families which are often used in traditional medicine. N-alkylamides (NAAs) are a large group of secondary metabolites occurring in more than 25 plant families, often used in traditional medicine and claimed to possess a diverse range of pharmacological activities such as antimicrobial, analgesic and anti-inflammatory properties [1,2,3,4,5,6,7,8]. Using in vitro Franz diffusion cell (FDC) experiments, it has already been shown that the N-alkylamide spilanthol can permeate the human skin and pig oral mucosa, reaching the systemic circulation after topical application [12,13,14]. Matthias et al [15] investigated the transport of mainly diene N-alkylamides from Echinacea (E. angustifolia and E. purpurea root) through a Caco-2 cell monolayer, which is a model of the intestinal barrier, and found that after 90 min, more than 50 % of the NAAs permeated through the monolayer
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