Quantitative In Vitro and In Vivo Evaluation of Intestinal and Blood-Brain Barrier Transport Kinetics of the Plant N-Alkylamide Pellitorine.

Lieselotte Veryser,Pratima Tatke,Nathalie Bracke,Bart De Spiegeleer,Tanmayee Joshi,Lien Taevernier,Evelien Wynendaele

doi:10.1155/2016/5497402

Abstract

Objective. To evaluate the gut mucosa and blood-brain barrier (BBB) pharmacokinetic permeability properties of the plant N-alkylamide pellitorine. Methods. Pure pellitorine and an Anacyclus pyrethrum extract were used to investigate the permeation of pellitorine through (1) a Caco-2 cell monolayer, (2) the rat gut after oral administration, and (3) the BBB in mice after intravenous and intracerebroventricular administration. A validated bioanalytical UPLC-MS2 method was used to quantify pellitorine. Results. Pellitorine was able to cross the Caco-2 cell monolayer from the apical-to-basolateral and from the basolateral-to-apical side with apparent permeability coefficients between 0.6 · 10−5 and 4.8 · 10−5 cm/h and between 0.3 · 10−5 and 5.8 · 10−5 cm/h, respectively. In rats, a serum elimination rate constant of 0.3 h−1 was obtained. Intravenous injection of pellitorine in mice resulted in a rapid and high permeation of pellitorine through the BBB with a unidirectional influx rate constant of 153 μL/(g·min). In particular, 97% of pellitorine reached the brain tissue, while only 3% remained in the brain capillaries. An efflux transfer constant of 0.05 min−1 was obtained. Conclusion. Pellitorine shows a good gut permeation and rapidly permeates the BBB once in the blood, indicating a possible role in the treatment of central nervous system diseases.

Highlights

Pellitorine (deca-2E,4E-dienoic acid isobutylamide, F3M1 according to the FxMy classification of N-alkylamides (NAAs)) is a highly abundant and biologically potent diene NAA found in Asteraceae plants such as Anacyclus pyrethrum (AP) [1]
Our results demonstrated that pellitorine was able to permeate the Caco-2 cell monolayer in both directions: from the apical-to-basolateral side and from the basolateral-to-apical side
In the basolateral to apical direction, the percentage of pellitorine which permeated through the Caco-2 cells after 120 min is 23.7% with DS1 and 1.84% with DS2

Summary

Introduction

Pellitorine (deca-2E,4E-dienoic acid isobutylamide, F3M1 according to the FxMy classification of N-alkylamides (NAAs)) is a highly abundant and biologically potent diene NAA found in Asteraceae plants such as Anacyclus pyrethrum (AP) [1]. Various pharmacological activities of pellitorine have already been reported, namely, antiprotozoal, larvicide, antiseptic, antithrombotic, antituberculosis, antibacterial, anticancer, and antiplatelet aggregation properties and vascular barrier protective effects [2,3,4,5,6,7,8,9,10]. It was demonstrated that pellitorine reduces fatty acid uptake in vitro [11]. Antiseizure activity was demonstrated after intraperitoneally administration of 100–800 mg/kg of the chloroform fraction of Anacyclus pyrethrum roots to mice. Other studies with the Anacyclus pyrethrum extract in mice showed anticonvulsant and myorelaxation activities [12]. Another study with an ethanolic AP root extract showed anticonvulsant effect against maximal electro shock (MES) induced convulsions in mice [13]. Sujith et al [14] found that the AP root extract possesses antidepressant activity in albino Wister rats and improves the learning acquisition of rats

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Discussion

Conclusion