Pharmacokinetics and Safety of Intravenous, Intravesical, Rectal, Transdermal, and Vaginal Melatonin in Healthy Female Volunteers: A Cross-Over Study

Abstract

Introduction: We aimed to investigate the pharmacokinetic properties and safety of melatonin administered by alternative routes of administration. Methods: This study employed a cross-over design in healthy female volunteers. Twenty-five milligrams of melatonin was administered intravenously, intravesically, rectally, transdermally, and vaginally. Blood samples were collected at specified time points up to 24 h following intravenous, intravesical, rectal, and vaginal administration, and up to 48 h following transdermal administration. Plasma melatonin concentrations were determined by radioimmunoassay. Sedation was evaluated by a simple reactiontime test, and sleepiness was assessed by the Karolinska Sleepiness Scale. Adverse events were registered for each route of administration. Results: Ten participants were included. We documented a mean (SD) time to maximal concentration of 51 (29) min for intravesical, 24 (20) min for rectal, 21 (8) h for transdermal, and 147 (56) min for vaginal administration. The mean (SD) elimination half-life was 47 (6) min for intravenous, 58 (7) min for intravesical, 60 (18) min for rectal, 14.6 (11.1) h for transdermal, and 129 (17) min for vaginal administration. The mean (SD) bioavailability was 3.6 (1.9)% for intravesical, 36.0 (28.6)% for rectal, 10.0 (5.7)% for transdermal, and 97.8 (31.7)% for vaginal administration. No significant changes in reaction times were observed following administration of melatonin by any of the administration routes. Increased tiredness was documented following transdermal administration only. No serious adverse effects were documented. Conclusion: Rectally and vaginally administered melatonin may serve as relevant alternatives to standard oral melatonin therapy. Transdermal delivery of melatonin displayed an extended absorption and can be applied if prolonged effects are intended. Intravesical administration displayed, as expected, a very limited bioavailability. Melatonin administered by these routes of administration was safe.

Pro-Oxidative Effect of KIO3 and Protective Effect of Melatonin in the Thyroid—Comparison to Other Tissues

“…The physiological blood concentration of melatonin in humans is 0–20 pg/mL in the daytime and at night it reaches even 40–200 pg/mL and decreases with age (e.g., [ 56 ]). Exogenous melatonin is applied therapeutically in doses between 2 and 10 mg, and the highest dose of melatonin used in clinical trials was 25 mg [ 57 ]. The intravenous administration of melatonin at a dose of 25 mg resulted in a blood concentration of ~7.52 × 10 5 pg/mL [ 57 ].…”

Cumulative Protective Effect of Melatonin and Indole-3-Propionic Acid against KIO3—Induced Lipid Peroxidation in Porcine Thyroid

“…As it was mentioned in the Introduction, exogenous melatonin is applied therapeutically in doses between 2 and 10 mg. In available studies the highest dose of melatonin used in clinical trials was 25 mg [ 51 ]. The intravenous administration of melatonin in a dose of 25 mg resulted in blood concentration of ~7.52 × 10 5 pg/mL [ 51 ].…”

“…In available studies the highest dose of melatonin used in clinical trials was 25 mg [ 51 ]. The intravenous administration of melatonin in a dose of 25 mg resulted in blood concentration of ~7.52 × 10 5 pg/mL [ 51 ]. In another study melatonin used in a dose of 10 mg intravenously resulted in blood concentration of ~3.9 × 10 5 pg/mL and when used orally, in concentration of ~3.5 × 10 3 pg/mL [ 52 ].…”

Anti-Warburg Effect of Melatonin: A Proposed Mechanism to Explain its Inhibition of Multiple Diseases

“…The safety of melatonin has been thoroughly examined [ 236 , 237 ]. It is not a foreign substance for humans (or any vertebrate species) since it is endogenously produced.…”