The Absolute Bioavailability of Oral Melatonin

Department of Medicine, Bassett Healthcare, Cooperstown, New York 13326, USA.
The Journal of Clinical Pharmacology (Impact Factor: 2.48). 08/2000; 40(7):781-4. DOI: 10.1177/00912700022009422
Source: PubMed


The absolute bioavailability of oral melatonin tablets was studied in 12 normal healthy volunteers. Subjects were administered, in a randomized crossover fashion, melatonin 2 mg intravenously and 2 and 4 mg orally. Blood was sampled over approximately eight (estimated) half-lives. Both the 2 and the 4 mg oral dosages showed an absolute bioavailability of approximately 15%. No difference in serum half-life was seen in any of the study phases. Oral melatonin tablets in dosages of 2 and 4 mg show poor absolute bioavailability, either due to poor oral absorption, large first-pass metabolism, or a combination of both. Further studies examining larger doses, in an attempt to saturate first-pass metabolism if it occurs, may be warranted.

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    • "In humans, orally administered melatonin exhibits extensive first-pass metabolism and its absolute bioavailability is reported to be around 15% with a wide range of variability (Di et al 1997; DeMuro et al 2000). The wide variations in melatonin´s bioavailability is attributed to inter-individual variations in the expression of and activity of CYPA2 and CYP1A (Hartter et al 2001). "
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    ABSTRACT: From a physiological perspective the sleep-wake cycle can be envisioned as a sequence of three physiological states (wakefulness, non-rapid eye movement, NREM, sleep and REM sleep) which are defined by a particular neuroendocrine-immune profile regulating the metabolic balance, body weight and inflammatory responses. Sleep deprivation and circadian disruption in contemporary "24/7 Society" lead to the predominance of pro-orexic and proinflammatory mechanisms that contribute to a pandemic metabolic syndrome (MS) including obesity, diabetes and atherosclerotic disease. Thus, a successful management of MS may require a drug that besides antagonizing the trigger factors of MS could also correct a disturbed sleep-wake rhythm. This review deals with the analysis of the therapeutic validity of melatonin in MS. Melatonin is an effective chronobiotic agent changing the phase and amplitude of the sleep/wake rhythm and having cytoprotective and immunomodulatory properties useful to prevent a number of MS sequels. Several studies support that melatonin can prevent hyperadiposity in animal models of obesity. Melatonin at a low dose (2-5 mg/day) has been used for improving sleep in patients with insomnia and circadian rhythm sleep disorders. More recently, attention has been focused on the development of potent melatonin analogs with prolonged effects (ramelteon, agomelatine, tasimelteon, TK 301). In clinical trials these analogs were employed in doses considerably higher than those usually employed for melatonin. In view that the relative potencies of the analogs are higher than that of the natural compound, clinical trials employing melatonin doses in the range of 50-100 mg/day are needed to assess its therapeutic value in MS.
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    • "Melatonin pharmacokinetics show low bioavailability (15%) in the bloodstream after oral administration. In addition, at low dose there is variable absorption and metabolism of the drug among individuals due to variable CYP1A2 activity before the drug enters into blood stream [7] making oral dose control difficult. High performance liquid chromatography (HPLC) with fluorescent detection has been used for melatonin analysis at low concentrations in plasma samples using an automated solid-phase extraction (SPE) system. "
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    ABSTRACT: The pharmacokinetic study of melatonin uptake requires a validated bioanalytical method for analysis. This study developed and validated a method for determination of melatonin in human plasma by high-performance liquid chromatography (HPLC)-fluorescence detector. Human plasma (100 uL) was extracted by liquid-phase extraction using dichloromethane (500 μL). An internal standard (N-acetylserotonin) was also used. After shaking, equilibration, separation of the layers and dying under nitrogen gas, the residue was redissolved in 50 μL of 100% acetonitrile and 40 μL of sample was injected into a 20 μL loop of the HPLC system. Separation was carried out on a HiQ Sil C18V column (5 μm, 250 mm x 4.6 mm) with 25% acetonitrile/phosphate buffer, pH 7.0 with a flow rate of 1.0 mL/min. Fluorescence excitation and emission wavelengths were set to 286 nm and 346 nm, respectively. Retention time of N-acetylserotonin and melatonin standard were approximately 5 and 9 minutes, respectively. The coefficient of variation (CV) of retention time was 0.4% with no interferences from other endogenous species. Linearity of melatonin standard was 0.9998, %CV of precision was 3.7%, and recovery was 96.3 to 101.5% with %CV 5.2–6.7% over a range of 7.2–180 ng/mL. Inter-day and inter-day precision were 4.8% and 5.9%, respectively. The limit of detection was 3 ng/mL and limit of quantification was 10 ng/mL. The method will be applied to pharmacokinetics study of novel melatonin delivery formulations using rats.
    Full-text · Conference Paper · Mar 2011
    • "We started with 2 mg, 30–40 min before planned sleep with the sleep routine timed around this. As oral melatonin can have variable and poor bioavailability (DeMuro et al. 2000), upwards titration of dose was allowed. The dose was increased by the parent every three nights by 2 mg to a maximum dose of 10 mg. "
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    ABSTRACT: Twenty-two children with autism spectrum disorders who had not responded to supported behaviour management strategies for severe dysomnias entered a double blind, randomised, controlled crossover trial involving 3 months of placebo versus 3 months of melatonin to a maximum dose of 10 mg. 17 children completed the study. There were no significant differences between sleep variables at baseline. Melatonin significantly improved sleep latency (by an average of 47 min) and total sleep (by an average of 52 min) compared to placebo, but not number of night wakenings. The side effect profile was low and not significantly different between the two arms.
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