This cohort crossover study demonstrated a t max of 41 min following oral administration. C max and AUC varied extensively between volunteers in both administration routes. Elimination half-lives were 54 min and 39 min, respectively. Bioavailability of oral melatonin was only 3 %, but demonstrated substantial inter-individual differences.

Oral melatonin

Oral melatonin was absorbed by first-order kinetics, which has previously been demonstrated in doses up to 80 mg [8]. The short t 1/2 absorption of 6 min, corroborate studies, applying similar oral drug formulations [8]. Accordingly, our t max value of 41 min is in agreement with other studies, documenting values ranging from 30 to 60 min [6, 11]. Oral administration of exogenous melatonin, approximately 45 min before intended onset of clinical effects therefore seems reasonable, assuming that clinical efficacy coincides with t max values [12]. Oral administration was associated with extremely variable C max and AUC 0-∞ oral values, which has been described previously [5]. The inter-individual variations are apparently caused by differences in absorption, distribution, metabolism or excretion of the drug, but the exact causes and clinical implications remain unestablished so far [5]. Previous studies demonstrate t 1/2 elimination values ranging from 46 to 65 min in oral doses from 0.5 to 6 mg [5, 6, 11], which correlates with our findings of 54 min. Our data demonstrated a very low absolute bioavailability of 3 %, albeit with a substantial inter-individual variability. Previous experimental studies have documented higher values ranging between 9 and 33 %, although with comparable inter-individual variability [5, 6, 12]. It is well established in both animal- and human studies that the low bioavailability results from an extensive hepatic first pass metabolism [5]. Similarly, it is also clear that these findings may mandate future dose regulations between different administration routes. However, a general lack of experimental- and clinical studies correlating melatonin plasma concentration levels and clinical effects still remains, and further knowledge is needed, preferably by in-depth pharmacokinetic-pharmacodynamic modelling.

Intravenous melatonin

Previous studies investigating iv administration of melatonin have also demonstrated first-order eliminations kinetics [10], as observed in our study. 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. Similarly, previous studies document CL values of 0.013 l min-1 kg-1 (weight-corrected) [13] and 0.027 l min-1 kg-1 [10], which correspond well to our findings of 0.022 l min-1 kg-1. Cavallo and colleagues also documented a V D of 1.8 l kg-1 [10], which is comparable with a value of 1.2 l kg-1, demonstrated in our study.

Strengths

Our study is the first to perform direct comparisons of pharmacokinetics of oral and iv melatonin in doses routinely administered perioperatively (approximately 10 mg) [2]. The study was performed as a crossover study to reduce the effect of the inter-individual variability on pharmacokinetic data. Our experimental setup included multiple blood samples for a detailed description of both absorption and elimination phases in both administration routes. Our study also included standard pharmacokinetic methods, such as “the method of residuals” and compartmental analysis [8, 10]. In addition, we chose to include the coefficient of determination (R2) to document the “goodness of fit” of the individual linear regression lines in the compartmental analysis. Our data demonstrated a R2 value of 0.96, indicating a high degree of “fit” of the first-order pharmacokinetic model, and, hence, a considerable accuracy of the derived pharmacokinetic variables.

Limitations

First, this study only included healthy male volunteers in an experimental setup. Hence, a potential gender difference in pharmacokinetic variables may exist. Furthermore, previous experimental studies indicate that the pharmacokinetics of melatonin is affected by age [10] and external factors, such as caffeine intake [14] cigarette smoking [15] and the use of oral contraceptives [16]. Also, a low number of clinical studies have demonstrated altered pharmacokinetic variables of melatonin [17–19] in e.g. critically ill patients [17, 18]. Interestingly, most other patient groups, e.g. surgical patients, still remain to be investigated. Comorbidity and drug interactions may change the pharmacokinetics of melatonin, potentially altering clinical efficacy of the drug [20].

Second, oral and iv study sessions were separated by 3 to 9 months for each volunteer. These time periods may theoretically have affected the comparability of individual pharmacokinetic variables, despite the crossover design. It, however, seems unlikely, as all volunteers were healthy young males in stable physical conditions.