Citrulline: from metabolism to therapeutic use.: citrulline: metabolism and therapeutic

International audienceCitrulline possesses a highly specific metabolism that bypasses splanchnic extraction because it is not used by the intestine or taken up by the liver. The administration of citrulline may be used to deliver available nitrogen for protein homeostasis in peripheral tissues and as an arginine precursor synthesized de novo in the kidneys and endothelial and immune cells. Fresh research has shown that citrulline is efficiently transported across the intestinal luminal membrane by a set of transporters belonging to the B⁰,⁺, L, and b⁰,⁺ systems. Several pharmacokinetic studies have confirmed that citrulline is efficiently absorbed when administered orally. Oral citrulline could be used to deliver arginine to the systemic circulation or as a protein anabolic agent in specific clinical situations, because recent data have suggested that citrulline, although not a component of proteins, stimulates protein synthesis in skeletal muscle through the mammalian target of rapamycin signaling pathway. Hence, citrulline could play a pivotal role in maintaining protein homeostasis and is a promising pharmaconutrient in nutritional support strategies for malnourished patients, especially in aging and sarcopenia

Contribution à une étude biopharmaceutique de la citrulline

L administration entérale de la citrulline (Cit) peut être avantageuse dans certaines situations d insuffisance intestinale. La Cit représente une source d arginine disponible pour la synthèse protéique dans les tissus. L objectif de notre travail est de supplémenter les patients en citrulline afin d améliorer leur statut nutritionnel. Cependant, la biodisponibilité tissulaire et l action de la Cit sont conditionnées par son absorption intestinale. Nous avons montré, en utilisant les cellules Caco-2 comme modèle d étude du transport intestinal, que la Cit est captée par les cellules entérocytaires grâce à deux types de transporteurs, un Na+-dépendant (Système B0,+) et deux Na+- indépendants (Systèmes L et b0,+). Ce nombre important de systèmes de transport pourrait compenser le faible taux de Cit dans l alimentation afin d améliorer sa disponibilité dans l organisme. Notre deuxième objectif a été de contourner l intestin et d atteindre directement le côlon pour administrer la Cit. Nous avons élaboré des formes galéniques par microencaspsulation en utilisant deux techniques différentes : le spray drying et la formulation de microsphères de pectinate de calcium par cross-linking . La technique de spray drying a abouti à la formulation de microsphères ayant de bonnes propriétés physiques en termes de morphologie et de taille, en revanche la libération de la Cit a été rapide en milieu gastrique. La formulation de microsphères de pectinate de calcium a permis d améliorer le contrôle de la libération de la Cit dans le milieu gastrique en réduisant le pourcentage de dissolution des microsphères à pH acide et de prolonger la durée de libération de la Cit au niveau coliqueCitrulline (Cit) is a major precursor of arginine by de novo synthesis in the kidneys. Thus, oral Cit supplementation may be beneficial in situations of intestinal failure. However, Cit bioavailability depends on its intestinal absorption. Since the mechanism of Cit transport across the intestine has not been established yet, this study was first designed to characterize Cit uptake by enterocytes. We have demonstrated, using Caco-2 cells as a model of intestinal transport, that citrulline uptake is mediated by the Na+-dependent carrier system B0,+ and two Na+- independent carriers : systems L and b0,+. The second aim of this work was to bypass the intestine and reach the colon directly to administer Cit; since intestinal absorption is reduced in patients with intestinal failure. For this purpose, we have developed microspheres by using two different techniques of microencapsulation: the spray drying technique and the formulation of calcium pectinate microspheres intented for colonic drug delivery. The spray drying technique led to the formulation of microspheres with suitable physical properties in terms of size and morphology; however the release of Cit has been rapid in the stomach. The formulation of calcium pectinate microspheres improved the control of Cit release by reducing its release at acidic pHPARIS-BIUP (751062107) / SudocSudocFranceF