Pharmacokinetics Of Melatonin Research Articles

Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder.

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin’s effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

Lack of Effect of Oral Melatonin on Platelet Parameters in Normal Healthy Dogs.

A randomized, prospective, blinded, placebo-controlled study on the effect of oral melatonin on platelet parameters was performed on 40 healthy dogs with normal physical examinations and no clinically significant findings on serum chemistry evaluation. Dogs were randomly assigned to the study group or the placebo-control group and administered oral melatonin or an oral inert tablet, respectively, for 28 days. Dogs in the study group were administered melatonin at 3 mg per os q 12 hr for dogs weighing <15 kg and 6 mg per os q 12 hr for dogs weighing 15 kg or more. Complete blood counts were obtained at 0, 7, 14, and 28 days of medication administration. No adverse effects or sedation were noted in any dog. The placebo group had a statistically significant transient increase in both plateletcrit and mean platelet volume on day 7 relative to baseline, which was not observed in the melatonin group. Oral melatonin did not appear to have a direct thrombopoietic effect in normal healthy dogs. Future studies are required to investigate the pharmacokinetics of melatonin in dogs and the potential benefits of melatonin in both thrombocytopenia and immune-mediated diseases.

Melatonin Pharmacokinetics Following Oral Administration in Preterm Neonates.

Melatonin possesses potential efficacy in perinatal brain injuries, and has been proposed as adjunctive pharmacological therapy in combination with hypothermia in the clinical setting. However, the pharmacokinetics of melatonin in preterm and term newborns is still unknown. The aim of this study was to analyze the pharmacokinetics of melatonin after intragastric administration in preterm infants. Preterm newborns were enrolled 24–72 h after birth, and randomly assigned to three groups receiving a single bolus of 0.5 mg·kg−1 melatonin, or 3 boluses of 1 or 5 mg·kg−1 of melatonin at 24-h intervals. Blood samples were collected before and at selective times after melatonin administration. The half-life of melatonin in plasma ranged from 7.98 to 10.94 h, and the area under the curve (AUC) from 10.48 to 118.17 µg·mL−1·h−1. Our results indicate a different pharmacokinetic profile in premature newborns, compared to adults and experimental animals. The high peak plasma concentrations and the long half-life indicate that in the neonatal clinical setting, it is possible to obtain and maintain high serum concentrations using a single administration of melatonin repeated every 12/24 h.

Effects of Caffeic Acid and Quercetin on In Vitro Permeability, Metabolism and In Vivo Pharmacokinetics of Melatonin in Rats: Potential for Herb-Drug Interaction.

Melatonin is a popular dietary supplement and also considered as pharmaceutical product for sleep disorders. Caffeic acid and quercetin are widely distributed in leafy vegetables, fruits, tea extract, and both are used as natural antioxidant. There is an immense concern for health researchers to study the herb/food-drug interactions of melatonin. It is mainly metabolized by CYP1A2 in human so that herbs/foods containing cytochrome P450 (CYP) inhibitors can affect pharmacokinetics of melatonin. By considering pharmacokinetic aspects, the present study was undertaken to evaluate the effects of caffeic acid and quercetin on Caco-2 cells permeability, metabolism, CYP1A inhibition in vitro assay systems and a single dose pharmacokinetics of melatonin in vivo rats. The effects of caffeic acid and quercetin on melatonin permeability were tested in Caco-2 cells. Metabolic stability and CYP1A activity were investigated in rat liver microsomes (RLMs) using probe substrates (melatonin/phenacetinin vitro). Melatonin and phenacetin were incubated in RLMs with or without caffeic acid and quercetin, and the IC50 values were determined. The pharmacokinetics of melatonin conducted in rats after a single dose (15mg/kg) pre-treatment with caffeic acid, quercetin and caffeic acid plus quercetin followed by oral dose of melatonin at 5mg/kg. Analysis of all samples was with LC-MS/MS. Caffeic acid and quercetin did not alter Caco-2 permeability of melatonin in apical to basolateral direction and vice versa. Melatonin was metabolized in rat liver microsomes, which was inhibited by both caffeic acid and quercetin through CYP1A. The concomitant oral administration of melatonin along with 15mg/kg of caffeic acid or quercetin or caffeic acid plus quercetin significantly (p<0.05) increased the AUC0-t of melatonin by 30.0, 66.7 and 114.0%, respectively. The apparent oral rat plasma clearance (CL/F) of melatonin also decreased significantly (p<0.05) by 28.78, 47.87 and 50% in presence of caffeic acid, quercetin and caffeic acid plus quercetin, respectively. These findings suggest that caffeic acid and quercetin improved oral exposure of melatonin via CYP1A inhibition pathway.

Melatonin pharmacokinetics after transdermal administration changes according to the time of the day

Melatonin is a neurohormone with multiple and different actions, such as chronobiotic or antioxidant. Melatonin is usually orally administered, but dermal administration is also useful in dermatological diseases or as adjuvant to certain skin treatments. Here, we studied the variability of the pharmacokinetics of melatonin and its metabolite AFMK, when melatonin is transdermally administered to Hairless rat at two different times of day (Zeitgeber Time 4 (ZT4) and ZT16). Moreover, in order to obtain the bioavailability, kinetics after intravenous administration was also studied. In addition, a permeation study was carried out, at both ZTs, to test the amount of melatonin retained in the skin after transdermal administration. Results showed that pharmacokinetic parameters of melatonin administered exogenously depended on the time of the day. When intravenous data were fitted to a compartmental model, the extrapolated plasma concentration at time 0 and the area under the curve were higher at ZT4, while clearance, volumes of central and peripheral compartments and volume of distribution at the steady state were higher at ZT16. Transdermal administration was best fitted to a one-compartment model and tmax, half-life of absorption and area under the curve showed higher values at ZT4, while the absorption rate and constant of absorption were higher at ZT16. AFMK was detected in all cases, but no differences between the two ZTs were observed. Transdermal administration showed better bioavailability also at ZT4. Results indicate that time of day is a variable that should be taken into account when melatonin is transdermally administered.

Pharmacokinetics of Repeated Melatonin Drug Administrations Prior to and After Surgery.

Recent clinical studies have documented the analgesic, anti-inflammatory, antioxidative and anxiolytic effects of exogenous melatonin. The pharmacokinetic properties of melatonin have primarily been investigated in experimental studies. The aim of this study was to estimate the pharmacokinetics of melatonin in patients undergoing surgery and general anesthesia. The study was designed as a prospective, two-phase cohort study. Patients were candidates for subpectoral breast augmentation surgery, and surgical procedures were performed by a single surgeon. The perioperative treatment protocol was standardized between patients. During the study, each patient received two separate oral administrations of melatonin 10mg. Melatonin was administered 60min before surgery, and at 9:00 p.m. the evening after surgery. The pharmacokinetic variables absorption half-life (t ½ absorption), time to maximal plasma concentration (T max), maximal plasma concentration (C max), elimination half-life (t ½ elimination), and area under the melatonin plasma concentration-time curve from time zero to infinity (AUC ∞) were estimated for both study phases. Median (interquartile range) values of t ½ absorption and T max were significantly increased during the postoperative phase [10.8 (6.9-15.1)min; 90.0 (48.8-120.0)min] compared with perioperatively [9.5 (6.3-16.5)min; 30.0 (15.0-30.0)min] (p=0.034; p=0.002), respectively. C max values were significantly higher during surgery [5497.5 (2077.1-13,233.8) pg/ml] compared with postoperative values [2340.5 (1672.4-8871.4) pg/ml] (p=0.005). Correspondingly, t ½ elimination was significantly extended during the postoperative phase [103.5 (57.8-237.8)min] compared with the perioperative phase [60.5 (47.8-83.6)min] (p=0.015). AUC ∞ did not differ between the study phases (p>0.05). These preliminary results indicate that postoperative melatonin dose should be augmented compared with preoperative administration if corresponding melatonin plasma levels are intended. Furthermore, postoperative administration times should be advanced compared with preoperative administration.

Pharmacokinetics of Melatonin: The Missing Link in Clinical Efficacy?

Despite widespread clinical application of melatonin, several unanswered questions remain regarding the pharmacokinetics of this drug. This lack of knowledge may contribute to the inconsistency of results in previous clinical studies. Currently, a t max value of 30-45min and a t ½elimination of 45min are well established. Several questions relate to what constitutes a clinically effective plasma concentration, the choice of ideal administration route, and the optimal method of analysis. Furthermore, investigations of melatonin metabolites in humans are urgently needed in order to characterize their biological functions and the metabolic fates of these derivatives. Finally, pharmacokinetics in patients should be investigated further in order to reduce the risk of potential adverse effects, such as daytime sleepiness or unintended sedation.

Melatonin in Surgery and Critical Care Medicine

Administration of exogenous melatonin in surgical and critical care patients has been investigated for various clinical purposes. Studies have demonstrated that melatonin can be used for treatment of preoperative anxiety. The analgesic effect of melatonin is well documented in experimental studies, but still needs to be established further in human clinical studies. The sleep-regulating effects of melatonin in surgical and critical care patients remain unclear. Melatonin has been shown to reduce emergence delirium in the early postoperative period, but no evidence exists in relation to postoperative and intensive care delirium. Limited evidence exists with respect to reduction of oxidative stress in surgical patients. Melatonin has been shown to improve outcome in experimental sepsis models, but still needs to be documented further in human clinical studies. Mechanisms of actions need to be clarified and most importantly dose-response relationships should to be established within the specific procedures and indications. Finally, paramount issues remain in relation to administration form, dosage, timing of administration, and pharmacokinetics of melatonin in surgical and critical care patients.

Melatonin replacement therapy in preterm infants: the impact of pharmacokinetics

Evaluation of: Merchant NM, Azzopardi DV, Hawwa AF et al. Pharmacokinetics of melatonin in preterm infants. Br. J. Clin. Pharmacol. doi: 10.1111/bcp.12092 (2013) (Epub ahead of print).The paper by Merchant et al. demonstrates that the pharmacokinetic profile of melatonin differs in preterm infants from that of adults. The findings of this study can guide the necessary future preventive and therapeutic clinical trials on melatonin in preterm infants. These studies are urgently needed to further evaluate the protective potential of melatonin in preterm infants. Melatonin acts as a potent endogenous antioxidant agent that antagonizes oxidative stress, and melatonin replacement therapy could thereby prevent the development of many disorders and diseases that can afflict preterm infants such as sepsis, asphyxia, respiratory distress or surgical complications. Since preterm infants are melatonin deficient, administration of the compound may provide the necessary levels to assure their health and well-being. Pharmacokinetic data such as those provided in the evaluated paper are necessary to establish safe and efficient melatonin treatment regimens in this highly susceptible population.

Melatonin pharmacokinetics following two different oral surge‐sustained release doses in older adults

Melatonin is increasingly used for the treatment of sleep disorders. Surge-sustained formulations consisting of combined immediate release and controlled release dosing may mimic the endogenous melatonin physiologic profile. However, relatively little is known about the pharmacokinetic properties of low-dose (<0.5mg) and high-dose (>2mg) melatonin in a combined immediate release/controlled release dose, especially in older adults who may also exhibit altered melatonin disposition. To assess this, we conducted a randomized, double-blind, placebo-controlled study of low-dose (0.4mg) and high-dose (4.0mg) melatonin (25% immediate release+75% controlled release) in 27 older adults with insomnia complaints and low endogenous melatonin levels to determine whether melatonin pharmacokinetic properties differ between these two doses. The time to maximum level (1.3hrs versus 1.5hrs), elimination half-life (1.8hrs versus 2.1hrs), and apparent total clearance (379L/hr versus 478L/hr) did not differ significantly between the low- and high-dose arms, respectively. The maximum concentration was 405 ±93pg/mL for the low-dose arm and 3999±700pg/mL for the high-dose arm, both of which are substantially higher than physiologic melatonin levels for this age group. In addition, subjects in the high-dose arm maintained melatonin levels >50pg/mL for an average of 10hrs, which could result in elevated melatonin levels beyond the typical sleep period. Renal and liver function parameters remained stable after 6wks of treatment. The linear pharmacokinetic behavior of melatonin observed in the elderly can form the basis for future studies exploring a wider range of dosing scenarios to establish exposure-response relationships for melatonin-mediated sleep outcomes.

Melatonin for sleep-disturbed children with autism spectrum disorders: can we really speak of a substitution treatment?

Dear Editor, In a recent article of this journal, Doyen et al. [2] provided a narrative review of melatonin use for sleep-disturbed children with autism spectrum disorders. In this very comprehensive work, the authors usefully summarized the pharmacokinetics of melatonin and its physiopathology in autism spectrum disorders, and discussed clinical trials in this population. In their very complete selection of publications, Doyen et al. considered 17 articles, from single case reports to randomized controlled trials. It must be noted, however, that eight of these studies mainly involved children with non-autistic neurodevelopmental disabilities (without providing subgroup analyses), or concerned children with Rett syndrome, a genetic disease whose affiliation to the autism spectrum is much questioned nowadays [1], and in which sleep problems generally differ from those seen in autism [5]. For these reasons, in a recent systematic review on the same topic, we limited our documentary sources to 12 of these 17 citations [4]. However, despite these discrepancies in the selection of literature, we came to the same conclusions than Doyen et al. that, although not evidencebased for now (considering the small number of randomized controlled trials and their methodological limits), melatonin treatment for sleep problems in individuals with autism spectrum disorders has received very encouraging results. We also agreed with Doyen et al. that more studies are needed, particularly for the collection of long-term follow-up data [3]. In Doyen et al.’s article, the section which is devoted to the analysis of clinical trials is entitled ‘‘Melatonin substitution in autistic subjects with sleep disturbance’’ (our emphasis), and we now would like to focus our comment on whether melatonin treatment in this context really is a substitution or not. First, it must be noticed that, whereas melatonin deficiency has been repeatedly reported in individuals with autism spectrum disorders, its association with sleep disturbance in this population has never been demonstrated for now. Second, within all the trials reviewed by Doyen et al.—and if we put aside Rett syndrome—no patient with an autism spectrum condition had a documented melatonin deficiency. Finally, 11 of these 17 studies included melatonin doses escalation up to 5 mg per day and more, which—as indicated by Doyen et al. later in their paper—lead to melatonin blood levels incommensurable to the physiological ones. For all these reasons, we believe that melatonin use in sleep-disturbed individuals with autism spectrum disorders cannot yet be considered as a substitution treatment. In fact, as Doyen et al. wrote in their discussion, the mechanisms by which melatonin improves sleep in many individuals with autism spectrum disorders remain unknown. Although some authors have hypothesized that these beneficial effects may proceed from the chronobiotic properties of melatonin, this hypothesis has not been proven for now and some arguments suggest that hypnotic effects may be involved (like for example the fact that the clinical benefits of melatonin are often seen from the first day of treatment). Indeed, it is well demonstrated that F. Guenole J.-M. Baleyte CHU de Caen, Service de psychiatrie de l’enfant et de l’adolescent, 14000 Caen, France

Dose finding of melatonin for chronic idiopathic childhood sleep onset insomnia: an RCT

RationalePharmacokinetics of melatonin in children might differ from that in adults.ObjectivesThis study aims to establish a dose–response relationship for melatonin in advancing dim light melatonin onset (DLMO), sleep onset (SO), and reducing sleep onset latency (SOL) in children between 6 and 12 years with chronic sleep onset insomnia (CSOI).MethodsThe method used for this study is the randomized, placebo-controlled double-blind trial. Children with CSOI (n = 72) received either melatonin 0.05, 0.1, and 0.15 mg/kg or placebo during 1 week. Sleep was assessed with log and actigraphy during this week and the week before. Outcomes were the shifts in DLMO, SO, and SOL.ResultsTreatment with melatonin significantly advanced SO and DLMO by approximately 1 h and decreased SOL by 35 min. Within the three melatonin groups, effect size was not different, but the circadian time of administration (TOA) correlated significantly with treatment effect on DLMO (r s = −0.33, p = 0.022) and SO (r s = −0.38, p = 0.004), whereas clock TOA was correlated with SO shift (r = −0.35, p = 0.006) and not with DLMO shift.ConclusionsNo dose–response relationship of melatonin with SO, SOL, and DLMO is found within a dosage range of 0.05–0.15 mg/kg. The effect of exogenous melatonin on SO, SOL, and DLMO increases with an earlier circadian TOA. The soporific effects of melatonin enhance the SO shift. This study demonstrates that melatonin for treatment of CSOI in children is effective in a dosage of 0.05 mg/kg given at least 1 to 2 h before DLMO and before desired bedtime.

A population Pharmacokinetic Turnover and Surge‐Function Model for Describing Melatonin Biological Rhythm in Healthy Male Subjects

A turnover model in combination with an empirical surge function based on a chromatographic peak detection algorithm was used to model the population pharmacokinetics of melatonin in 32 healthy males (aged 20–30 years, weight 62–85 kg) who had 15 blood samples drawn (11:00 to 08:00) on three occasions, separated by 2–4 weeks. Serum melatonin concentrations were measured by RIA. A pharmacokinetic model with a surge function was fitted to the data; dA/dt = KIN [1 + (AMP/(((t − T0)/WID)N + 1))] − KOUTA, using NONMEM. Estimates were sought for the typical population parameter values and the intersubject variability (CV%) of; baseline amount of melatonin (AB), elimination rate constant (KOUT), peak amplitude (AMP), peak width (WID), acrophase (T0). The model stability was validated using a nonparametric bootstrap (100 samples with replacement). Population typical values (CV%) were: AB; 103 ng (103%), KOUT; 0.255 h−1 (57.8%), AMP; 34.9 (108%), WID; 2.3 h (20.9%), T0; 14.8 h (4.4%). Interoccasion variability (CV%) for; AB (12.3%), KOUT (29.5%) and AMP (9.1%) was much less than the corresponding intersubject variability. This approach has potential for application in clinical studies designed to characterize abnormal melatonin rhythms. © 2008 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:782–790, 2008

The Effect of Oral Contraceptives on the Pharmacokinetics of Melatonin in Healthy Subjects With CYP1A2 g.‐163C&gt;A Polymorphism

The effect of oral contraceptives (OCs) on melatonin metabolism was studied in 29 subjects genotyped for CYP1A2 SNP g.-163C>A polymorphism. Plasma melatonin and 6-OH-melatonin concentrations were measured after a 6-mg dose of melatonin using a validated liquid chromatography/mass spectrometry method. The mean melatonin AUC and C(max) values were 4- to 5-fold higher in OC users than in non-OC users (P < .0001), whereas the weight-adjusted clearance was significantly lower in OC users (P < .0001). No significant difference in melatonin pharmacokinetics between the genotypes and no additional effect by the genotype on the OC-induced increase in melatonin exposure were evident. Melatonin exposure had no significant effect on the subjects' state of alertness. In conclusion, a significant inhibitory effect of OCs on the CYP1A2-catalyzed melatonin metabolism was seen; thereby, OC use can alter CYP1A2-phenotyping results.

Melatonin Pharmacokinetics in Premenopausal and Postmenopausal Healthy Female Volunteers

Melatonin Pharmacokinetics in Premenopausal and Postmenopausal Healthy Female Volunteers

Solid Lipid Nanoparticles Incorporating Melatonin as New Model for Sustained Oral and Transdermal Delivery Systems

melatonin (MT) is a hormone produced by the pineal gland at night, involved in the regulation of circadian rhythms. For clinical purposes, exogenous MT administration should mimic the typical nocturnal endogenous MT levels, but its pharmacokinetics is not favourable due to short half-life of elimination. Aim of this study is to examine pharmacokinetics of MT incorporated in solid lipid nanoparticles (SLN), administered by oral and transdermal route. SLN peculiarity consists in the possibility of acting as a reservoir, permitting a constant and prolonged release of the drugs included. In 7 healthy subjects SLN incorporating MT 3 mg (MT-SLN-O) were orally administered at 8.30 a.m. MT 3 mg in standard formulation (MT-S) was then administered to the same subjects after one week at 8.30 a.m. as controls. In 10 healthy subjects SLN incorporating MT were administered transdermally (MT-SLN-TD) by the application of a patch at 8.30 a.m. for 24 hours. Compared to MT-S, Tmax after MT-SLN-O administration resulted delayed of about 20 minutes, while mean AUC and mean half life of elimination was significantly higher (respectively 169944.7 +/- 64954.4 pg/ml x hour vs. 85148.4 +/- 50642.6 pg/ml x hour, p = 0.018 and 93.1 +/- 37.1 min vs. 48.2 +/- 8.9 min, p = 0.009). MT absorption and elimination after MT-SLN-TD demonstrated to be slow (mean half life of absorption: 5.3 +/- 1.3 hours; mean half life of elimination: 24.6 +/- 12.0 hours), so MT plasma levels above 50 pg/ml were maintained for at least 24 hours. This study demonstrates a significant absorption of MT incorporated in SLN, with detectable plasma level achieved for several hours in particular after transdermal administration. As dosages and concentrations of drugs included in SLN can be varied, different plasma level profile could be obtained, so disclosing new possibilities for sustained delivery systems.

Intranasal absorption of melatonin in vivo bioavailability study

The bioavailability of melatonin in rabbits after nasal administration of two formulations has been studied. In each case, a total amount of 1.5 mg melatonin in 50 μl was administered and compared with 1.5 mg i.v. The test solutions were formulated with 40% polyethylene glycol 300 (PEG 300), one with 1% sodium glycocholate (+GC) and one without (−GC). The bioavailability for +GC was 94% (S.D.±29%, n=4), whereas the bioavailability for −GC was 55% (S.D.±17%, n=6). These results indicate that GC has an enhancer effect ( P<0.05). However, the relatively high bioavailability without GC shows that it might not be necessary to use an enhancer for a clinical relevant formulation. The pharmacokinetics of melatonin could be described by a one-compartment model, and the serum half-life was about 13 min. The absorption rate for both formulations was very fast ( t max=5 min) and C max mean was 493±290 ng/ml ( n=4) and 249±125 ng/ml ( n=6) for +GC and −GC, respectively.

Pharmacokinetics and oral bioavailability of exogenous melatonin in preclinical animal models and clinical implications.

A review of the literature indicates that the absolute oral bioavailability of exogenous melatonin in humans or in preclinical animal models has not been adequately characterized; hence, this study was undertaken. Pharmacokinetics of melatonin was studied in rats, dogs, and monkeys following intravenous and oral administrations, and the absolute oral bioavailability of melatonin was calculated from the area under the plasma concentration-time curve. The apparent elimination half-life of melatonin following an intravenous dose of 3 mg/kg (5 mg/kg in rats) was 19.8, 18.6, and 34.2 minutes, respectively, in rats, dogs, and monkeys. The dose normalized oral bioavailability of melatonin following a 10 mg/kg oral dose was 53.5% in rats, while it was in excess of 100% in dogs and monkeys. Further, bioavailability of melatonin following a 10 mg/kg intraperitoneal administration in rats was 74.0%, suggesting the lack of substantial first-pass hepatic extraction of melatonin in rats. However, the oral bioavailability of melatonin in dogs decreased to 16.9% following a 1 mg/kg oral dose, indicating dose-dependent bioavailability in dogs. In vitro permeability studies with CACO-2 cells suggest that melatonin is likely to be well absorbed in humans. In vitro metabolism studies with fresh liver slices from rats as well as human donors were conducted to compare the initial rates of metabolism of melatonin between the two species and the results suggest that the intrinsic clearance of melatonin in humans may be lower than that in rats.

PET and plasma pharmacokinetic studies after bolus intravenous administration of [ 11C]melatonin in humans

A human PET study was performed with carbon-11 labelled melatonin in a healthy volunteer. Plasma pharmacokinetics of melatonin and 6-sulfatoxymelatonin were simultaneously determined using radioimmunoassay. Analysis of tracer kinetics showed maximum activity in the brain 8.5 min following injection, which was different from the curve observed for the plasma radioactivity (maximum at 3.5 min). The results confirmed that melatonin readily crosses the blood-brain barrier and that 6-sulfatoxymelatonin is the main plasma metabolite. The distribution of tracer as a function of time in this study failed to reveal any specific binding.

Pharmacokinetics of melatonin in man after intravenous infusion and bolus injection

The pharmacokinetics of melatonin during the day-time has been studied in 4 healthy subjects after a bolus i.v. injection of 5 or 10 micrograms/person and after a 5 h infusion of 20 micrograms per person in 6 healthy subjects. In addition, a pinealomectomized patient whose nocturnal plasma melatonin had been abolished was investigated after the i.v. infusion--once during the night and once during the day. The clearance of melatonin from blood showed a biexponential decay. The pharmacokinetic parameters in the two studies were similar, except for the disappearance rate constant beta and the apparent volume of distribution at steady-state (Vss). Supplementary peaks or troughs were superimposed on the plateau and the falling part of the profile. They were not due to stimulation of endogenous secretion, because they were also seen in the pinealomectomized patient. During the melatonin infusion, the plasma hormone level reached a steady-state after 60 and 120 min, and when it was equal to the nocturnal level. The infusion regime may be valuable in replacing blunted hormonal secretion in disease states.