title: Melatonin pharmacokinetics after transdermal administration changes according to the time of the day.
abstract: 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.
authors.affiliation: Departament de Farmàcia i Tecnologia Farmacèutica, Facultat de Farmàcia i Ciències de la Alimentació, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Flo
authors.affiliation: Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de la Alimentació, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain. Electronic address: cambras@ub.edu.
authors.forename: Trinitat
authors.initials: T
authors.lastname: Cambras
authors.affiliation: Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de la Alimentació, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Díez-Noguera
authors.affiliation: Departament de Farmàcia i Tecnologia Farmacèutica, Facultat de Farmàcia i Ciències de la Alimentació, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Calpena
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000493:pharmacokinetics; D001682:Biological Availability; D002909:Chronobiology Phenomena; D055870:Drug Chronotherapy; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D008550:Melatonin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D008954:Models, Biological; D054772:Rats, Hairless
chemical_list: D000975:Antioxidants; D008550:Melatonin
keywords: AFMK; Circadian; Hairless rats; Melatonin; Pharmacokinetics; Skin; Transdermal administration