The Absolute Bioavailability of Oral Melatonin

ArticleinThe Journal of Clinical Pharmacology 40(7):781-4 · August 2000with244 Reads
DOI: 10.1177/00912700022009422 · Source: PubMed
Abstract
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.
    • "As with oral melatonin, iv administrations displayed extensive variations in C max and AUC 0-∞ IV values, which is in accordance with previous studies [6]. Other studies also documented t 1/2 elimination values ranging between 28 and 60 min in iv doses from 0.005 mg to 2 mg [6, 10, 13], which corresponds to the 39 min, demonstrated in the present study. Several studies confirm that elimination rates of iv melatonin (and oral melatonin) are not related to the administered dose. "
    [Show abstract] [Hide abstract] ABSTRACT: The aim was to investigate the pharmacokinetics of oral and iv melatonin in healthy volunteers. The study was performed as a cohort crossover study. The volunteers received either 10 mg oral melatonin or 10 mg intravenous melatonin on two separate study days. Blood samples were collected at different time points following oral administration and short iv infusion, respectively. Plasma melatonin concentrations were determined by RIA technique. Pharmacokinetic analyses were performed by “the method of residuals” and compartmental analysis. The pharmacokinetic variables: k a , t 1/2 absorption , t max , C max , t 1/2 elimination, AUC 0-∞ , and bioavailability were determined for oral melatonin. C max , t 1/2 elimination , V d , CL and AUC 0-∞ were determined for intravenous melatonin. Twelve male volunteers completed the study. Baseline melatonin plasma levels did not differ significantly between the study days (P = 0.067). Mean (SD) t 1/2 absorption of oral melatonin was 6.0 (3.1) min. Mean t max was 40.8 (17.8) min with a median (IQR) C max of 3550.5 (2500.5–8057.5) pg ml -1 . Mean t 1/2 elimination was 53.7 (7.0) min. Median absolute bioavailability was 2.5 (1.7–4.7) %. Median C max after short iv infusion of melatonin was 389,875.0 (174,775.0–440,362.5) pg ml -1 . Mean t 1/2 elimination was 39.4 (3.6) min, mean V d 1.2 (0.6) l kg -1 and mean CL 0.0218 (0.0102) l min -1 kg -1 . This cohort crossover study estimated pharmacokinetics of oral and iv melatonin, respectively in healthy volunteers. Bioavailability of oral melatonin was only 3 %. Trial registration Eudra-CT number: 2013-000205-23 (initial registration 27.03.2013). Clinicaltrials.gov Identifier: NCT01923974 (initial registration 08.08.2013).
    Full-text · Article · Dec 2016
    • "In this study, we only analyzed the deviation of F based on the two-compartment model. As a result, 10 data sets, 2 of which were original data from published literature [6] and 8 of which were transformed from the plasma concentration-time graphs [5,[7][8][9][10][11][12], met the preconditions and were further analyzed. Information on the types of administration, doses, AUCs drugs after ev administration as well as absolute bioavailability were recorded for 10 selected studies (Table 2). "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose: Absolute bioavailability (F) is calculated as the ratio of the area under the plasma drug concentration-time curve (AUC) between extravascular administration and intravenous injection. However, as distribution of a drug after intravenous administration does not reach an equilibrium in the body during the distribution phase, the plasma drug concentration at this phase does not reflect the total amount of drug in the body. The goal of this paper was to analyze the insufficiencies of the method for calculating on absolute bioavailability and to propose a modification to improve the calculation. Methods: Literature reporting absolute bioavailability published during 1983-2014 was searched for ten drug candidates. Plasma drug concentrations representing the amount of drug in the body were then calculated at each time point during the distribution phase according to the plasma drug concentration-time relationship during the elimination phase. Results: The AUC values based on the distribution equilibrium drug concentrations following intravenous injection were 75%±11% of the actually measured drug concentrations in the literature. The absolute bioavailability values in the literature were 76%±12% of the actual bioavailability based on the AUCs from distribution-equilibrium drug concentrations. Conclusions: The present method underestimates the absolute drug bioavailability and should be modified to represent the data more accurately. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
    Article · May 2016
    • "Oral absorption of melatonin is rapid and peak plasma levels are achieved 20 to 60 min following ingestion. The plasma half-life of melatonin is short and it is rapidly cleared by the liver [3,24]. A variety of experimental evidence exists for the efficacy of melatonin in patients with circadian rhythm sleep disorders [3,4,25,26]. "
    [Show abstract] [Hide abstract] ABSTRACT: Circadin 2 mg prolonged-release tablet is the only licensed melatonin product available in the UK. Circadin is indicated for patients with primary insomnia aged 55 and over, but is more widely used "off-label" to treat sleep disorders especially in the paediatric population. Children and older people often have difficulty swallowing tablets and dividing the tablet is sometimes required to ease administration. The aim of this study was to measure the release profile of melatonin from Circadin tablets when divided or crushed, and compare this with release from intact tablets. Dissolution testing was also performed for unlicensed melatonin products for comparison. Dissolution tests were performed using the pharmacopoeial paddle apparatus, with melatonin release analyzed by high performance liquid chromatography. Melatonin content, hardness, friability, and disintegration of the products were also evaluated. The prolonged release of melatonin from Circadin tablets was unlike that of any other product tested. When divided into halves, Circadin preserved most of the prolonged-release characteristic (f2 = 58), whereas quarter-cut and crushed tablet had a more immediate melatonin release profile. Circadin is significantly less expensive and should be preferred to unlicensed medicines which are not pharmaceutically equivalent and offer less quality assurance.
    Full-text · Article · Jan 2016
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