Correspondence

Variable Bioavailability of Oral Melatonin

N Engl J Med 1997; 336:1028-1029April 3, 1997

Article

To the Editor:

It has been claimed that melatonin has many actions, mostly on the basis of uncontrolled studies of widely varying oral doses. It is commonly assumed that the administered dosage of melatonin bears a direct relation to its circulating concentration.

We estimated the bioavailability of oral melatonin by determining the pharmacokinetics of intravenous bolus and oral doses of melatonin (Sigma Chemical, St. Louis) in four normal men (21 to 32 years old), who were given 20 μg intravenously on one occasion and 500 μg orally on a second occasion, with an interval of at least one month between the two occasions. The study protocol was approved by the local ethics committee, and the men gave informed consent.

The mean (±SD) half-time of the elimination phase after oral administration was 47±3 minutes, but the peak plasma melatonin concentrations varied widely among the four men, ranging from 480 to 9200 ng per liter (2 to 39 nmol per liter). The bioavailability of oral melatonin, determined by comparing the intravenous and oral data,1 was poor (mean, 33 percent) and also varied among the men, ranging from 10 percent to 56 percent.

If the poor bioavailability of oral melatonin were simply a function of poor absorption, the ratio of melatonin to its principal hepatic metabolite,2,3 6-sulfatoxymelatonin, would be constant. However, we found a markedly increased area under the curve (AUC) for the ratio of 6-sulfatoxymelatonin to melatonin in plasma after oral as compared with intravenous administration (13±13 vs. 1±1), which can be explained only if one assumes that there was considerable first-pass hepatic extraction after oral administration, giving rise to the conversion of melatonin to 6-sulfatoxymelatonin and thereby decreasing the bioavailability of melatonin. Furthermore, there was a reciprocal relation between bioavailability and hepatic conversion. Two men had lower bioavailability (10 percent and 12 percent) and their AUC ratios were higher (31 and 14), whereas the other two men had higher bioavailability (56 percent and 54 percent) and their AUC ratios were lower (4 and 3). In other words, there was a clear inverse relation between the AUC ratio and bioavailability after oral melatonin administration, confirming that the low bioavailability was a consequence of hepatic first-pass extraction, which converts melatonin to its metabolite before it enters the systemic circulation.

These results demonstrate that the bioavailability of melatonin varies widely, and it is unlikely that the biologic effects of oral melatonin will be understood until its bioavailability is made less variable. There is no evidence to suggest that 6-sulfatoxymelatonin has any biologic activity.4

Wei-Li Di, M.D., Ph.D.
Aban Kadva, M.D.
Atholl Johnston, Ph.D.
Robert Silman, M.D., Ph.D.
St. Bartholomew's and the Royal London School of Medicine and Dentistry, London E1 1BB, United Kingdom

4 References

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