Pharmacokinetics of Alternative Administration Routes of Melatonin: A Systematic Review

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.

Systemic and transdermal melatonin administration prevents neuropathology in response to perinatal asphyxia in newborn lambs

“…In contrast, intravenous MLT administration every 2 hours induced a sustained increase in circulating MLT concentrations >600‐fold, and a further 2‐fold increase in the cerebral cortex compared with patch administration. In adult studies, the maximum concentrations of MLT are reached with transdermal patches between 1 and 18 hours following application . These human studies observed inconsistent concentrations of MLT between patches; generally, the higher dose patches showed a faster time to maximum concentration, for example 20‐100 mg patches produced a peak circulation at 1‐2 hours .…”

“…In adult studies, the maximum concentrations of MLT are reached with transdermal patches between 1 and 18 hours following application. [45][46][47][48][49]81 These human studies observed inconsistent concentrations of MLT between patches; generally, the higher dose patches showed a faster time to maximum concentration, for example 20-100 mg patches produced a peak circulation at 1-2 hours. 47 We undertook a small in vitro study to assess MLT release from the patches used in this study and found that MLT patches had a maximal diffusion rate of approximately 875 pg/mL/h (data not shown) reached at 2-4 hours, but this was highly variable.…”

Melatonin levels in human diabetic dental pulp tissue and its effects on dental pulp cells under hyperglycaemic conditions

“…, Zetner et al . ). In the oral cavity, MEL exhibits paracrine effects on nearby cells, acting as an antioxidant and anti‐inflammatory molecule, proved to be useful in protecting dental and periodontal tissues and preventing bone resorption by acting via NF‐kB signalling (Cutando et al .…”

“…MEL can be administered by several routes (orally, intraperitoneally, or locally directly in the effect-site e.g. in dental implants) with a very wide safety margin (Cutando et al 2008, Zetner et al 2016. In the oral cavity, MEL exhibits paracrine effects on nearby cells, acting as an antioxidant and anti-inflammatory molecule, proved to be useful in protecting dental and periodontal tissues and preventing bone resorption by acting via NF-kB signalling (Cutando et al 2007, Calvo-Guirado et al 2010.…”

Melatonin as a Food Supplement for Sleep Disorders

“…Slow release, prolonged release, and surge sustained preparations are designed to extend the time of high circulating melatonin [18]. Melatonin has low bioavailability, in general, although it has been found that transmucosal administration increases bioavailability [19]. A critical feature of exogenous melatonin with regard to its clinical uses is its very low toxicity and lack of addictive properties [20,21].…”