Pharmacokinetics

Melatonin has been administered orally and intravenously. Commercially available dietary supplement formulations of melatonin include oral and sublingual tablets, orally dissolving tablets, soft chews, capsules, teas, lozenges, and oral spray delivery systems. There have been reports of substantial variability in product purity and melatonin content of available products.

Melatonin administration follows a different pharmacokinetic profile than that of the endogenous hormone. Melatonin crosses the blood-brain barrier, and also traverses the placenta in pregnancy. Some accumulation of melatonin in fat tissue may occur with prolonged daily administration. The primary metabolic pathway occurs via the liver via oxidative metabolism via CYP1A (isoenzymes CYP1A2 and CYP1A1), with minor roles by CYP2C19 and possibly CYP2C9. The principal metabolite is 6-sulphatoxy-melatonin (6-S-MT), which is inactive. Elimination of melatonin is by renal excretion of metabolites, 89% as sulphated and glucoronide conjugates of 6-hydroxymelatonin and 2% is excreted as unchanged, active melatonin. The mean elimination half-life (T1/2) after oral administration of immediate-release melatonin is roughly 45 minutes; with intravenous administration, the half-life is approximately 28 minutes.(3) The terminal half-life is 3.5 to 4 hours and the excretion of the primary metabolite is completed within 12 hours following a single oral dose of an extended-release product.(2)

Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP1A1

Melatonin is primarily and predominantly metabolized by CYP1A2, with some metabolism by CYP1A1, CYP1B1, and minor contributions by CYP2C9 and CYP2C19. Melatonin may exhibit significant interactions with potent CYP1A2 inhibitors, such as fluvoxamine. Melatonin has been observed to induce CYP3A in vitro at supra-therapeutic concentrations only; the clinical relevance of the finding is unknown.(2)

Route-Specific Pharmacokinetics:

Oral Route: After oral administration, melatonin undergoes significant first-pass hepatic metabolism to 6-sulfaoxymelatonin, producing a melatonin bioavailability averages 15% (range: 9—33%); the time to maximum concentrations (Tmax) averages 50 minutes (range: 15 minutes to 210 minutes). Sublingual and oral spray delivery systems may result in greater melatonin bioavailability due to less first-pass metabolism.(3) The presence of food appears to delay the time to maximal absorption and lowers maximal concentration, so bedtime doses should be taken without food.(2)

Special Populations:

Hepatic Impairment: Melatonin is primarily and predominantly metabolized by oxidative hepatic metabolism. Plasma melatonin levels in patients with cirrhosis were significantly increased during daylight hours. Patients had a significantly decreased total excretion of 6-sulfatoxymelatonin (the major, inactive metabolite) compared with controls.(2)

Patients with hepatic impairment are recommended to consult their health care provider prior to melatonin use. Melatonin is primarily metabolized by oxidative hepatic metabolism. Published data demonstrates markedly elevated endogenous melatonin levels during daytime hours due to decreased clearance in patients with hepatic impairment. Therefore, exogenous use of melatonin is not recommended in patients with hepatic impairment.(2)

Renal Impairment: The effect of any stage of renal impairment on melatonin pharmacokinetics has not been sufficiently studied.(2) In patients with normal renal function, a minimal amount of melatonin is excreted unchanged in the urine. A clinical study in patients with renal impairment indicated there is no accumulation of melatonin after repeated daily dosing of 2 mg oral doses at bedtime.(2)

Geriatric: Melatonin metabolism is known to decline with age. Across a range of doses, higher exposure (AUC) and maximal concentrations (Cmax) have been reported in older patients compared to younger patients, reflecting the lower metabolism of melatonin in the elderly. The Cmax levels are approximately 500 pg/mL and the AUC 3000 pg x h/mL in younger adults versus a Cmax of approximately 1200 pg/mL and an AUC approximately 5000 pg x h/mL in elderly patients age 55 to 69 years.(2)

Gender Differences: A 3- to 4-fold increase in maximal concentration (Cmax) is apparent for adult women compared to men. However, no pharmacodynamic differences between males and females were found despite differences in blood levels.(2)

Smoking: Patients who are tobacco smokers have increased melatonin clearance due to the induction of CYP1A2 by tobacco.(2)(3)

Critically Ill patients: Critically ill patients appear to have altered melatonin absorption and clearance.