Physiologically-based pharmacokinetic simulations in pharmacotherapy: selection of the optimal administration route for exogenous melatonin

Abstract

<jats:p>&lt;p class="ADMETabstracttext"&gt;The benefits of melatonin on human body are drawing increasing attention from several researchers in different fields. While its role as cure for sleep disturbances (e.g., jet lag, insomnia) is well documented and established, new functions in physiological and pathophysiological processes are emerging. To investigate these effects, there is need for the characterization of melatonin transport processes in the body and resulting pharmacokinetics. Although recent works propose physiologically-based pharmacokinetic modelling of melatonin, no work has yet highlighted the potential of PBPK simulations to shed light on melatonin pharmacokinetic aspects and discrimination among administration routes. This paper presents, validates, and discusses a versatile PBPK model featuring different ways of administration and compares the resulting pharmacokinetic profiles of intravenous, oral, and transdermal administration, with the goal of understanding which is the optimal route to achieve either physiological and/or supraphysiological melatonin levels.&lt;/p&gt;</jats:p>

Binding and dynamics of melatonin at the interface of phosphatidylcholine-cholesterol membranes

“…The benefits of MEL in the human body have recently drawn much attention in different fields. MEL is a natural hormone secreted by the pineal gland well known to regulate biological rhythms [13], to induce sleep [14], and that can also contribute to protect the organism from Alzheimer disease [15]. MEL is reported to induce/promote complex antioxidative and DNA repair systems which make it a very good candidate for curing several dermatoses associated with substantial oxidative damage.…”

Microscopic Interactions of Melatonin, Serotonin and Tryptophan with Zwitterionic Phospholipid Membranes

“…Melatonin is a neurohormone that is produced in the pineal gland, first being isolated in 1958 by Lerner et al [ 29 ] after it was identified in bovine pineal extracts. There is evidence that MEL can regulate circadian rhythms [ 30 ] and mood, induce sleep [ 31 ], and contribute in protecting the organism from Alzheimer disease [ 32 ], having become one of most studied hormones in relation to its affectation to the human body [ 33 , 34 , 35 , 36 ]. MEL plays a role in aging processes, being mainly protective of oxidative stress and damage [ 37 ], and it is also related to skin pigmentation and DNA repair systems.…”

Physiologically based pharmacokinetic (PBPK) modeling and simulation in drug discovery and development

“…The model built in healthy subjects has been applied in disease-subjects as well as in subjects with liver or renal impairment. One other research article was titled "Physiologically-based pharmacokinetic simulations in pharmacotherapy: selection of the optimal administration route for exogenous melatonin" [ 7 ] where the authors showed the significance of PBPK model in dose optimization and selection of route of administration. One article of a great interest was a review entitled “PBPK modelling of highly lipid soluble and extracellular solutes” [ 8 ], which extensively discussed two classes of drugs, namely the highly lipid soluble (HLS) solutes, and the extracellular (ECS) solutes.…”