Pharmacokinetics of Alternative Administration Routes of Melatonin: A Systematic Review

Introduction ▼ Melatonin is a hormone produced by the pineal gland, regulating the circadian rhythm in mammals [1]. Exogenous administration of melatonin improves sleep quality [2], reduces jet lag [3], and possesses analgesic [4, 5], anti-oxidative [6, 7] and anti-inflammatory effects [6]. Melatonin is traditionally administered orally, but the drug displays a poor and variable bioavailability due to an extensive first pass metabolism [8–11]. In order to optimize tissue delivery of melatonin, alternative administration routes, other than oral and intravenous formulations, may be required. The aim of this study was to present an overview of studies investigating the pharmacokinetics of alternative administration routes of melatonin in animals and in humans. Materials and Methods ▼ This systematic review was conducted in accordance to the PRISMA and PRISMA-P guidelines [12, 13] (PROSPERO register, registration number: CRD42015017042). The literature search was performed on February 25th 2015 in PubMed and Embase databases. The review included experimental or clinical studies written in English, investigating pharmacokinetics of alternative administration routes of melatonin in vivo. Alternative administration routes were defined as all administration routes except oral and intravenous. Studies were identified using the search terms (((((pharmacokinetic) OR pharmacokinetics) OR bioavailability)) AND melatonin) AND ((((human) OR humans) OR animal) OR animals). The “all fields” setting was applied for all search terms. Furthermore, a manual “snowball” search was performed in the reference lists of the studies included. Abstract ▼ Background: Melatonin is traditionally administered orally but has a poor and variable bioavailability. This study aims to present an overview of studies investigating the pharmacokinetics of alternative administration routes of melatonin. Methods: A systematic literature search was performed and included experimental or clinical studies, investigating pharmacokinetics of alternative administration routes of melatonin in vivo. Alternative administration routes were defined as all administration routes except oral and intravenous. Results: 10 studies were included in the review. Intranasal administration exhibited a quick absorption rate and high bioavailability. Transdermal administration displayed a variable absorption rate and possible deposition of melatonin in the skin. Oral transmucosal administration of melatonin exhibited a high plasma concentration compared to oral administration. Subcutaneous injection of melatonin displayed a rapid absorption rate compared to oral administration. Conclusion: Intranasal administration of melatonin has a large potential, and more research in humans is warranted. Transdermal application of melatonin has a possible use in a local application, due to slow absorption and deposition in the skin. Oral transmucosal administration may potentially be a clinically relevant due to avoiding first-pass metabolism. Subcutaneous injection of melatonin did not document any advantages compared to other administration routes.