Circadian dosing time dependency in the forearm skin penetration of methyl and hexyl nicotinate.

The forearm skin penetration of hydrophilic methyl nicotinate (MN) and lipophilic hexyl nicotinate (HN) was assessed around the clock. The sixteen healthy women (median age: 22 years, weight: 57 kg and height: 162 cm) who volunteered for the study were synchronized with a diurnal activity from 07.00h (+/- 1h) to 23.00h (+/- 1h.30min) and a nocturnal rest before and during the 48h sojourn in air-conditioned rooms (26 degrees C +/- 0.5 degrees C). Both HN (0.5% ethanol solution) and MN (5% ethanol solution) have a vasodilative effect on dermal vessels. The lag time (LT) between the delivery of a fixed volume (10 microliters) of the agent at the skin surface and the beginning of the vasodilatation, detected with a laser-Doppler method, was used to quantify the penetration kinetics. Tests were performed every 4h, at fixed clock hours, over a span of a 40h. Two types of tests were done with each of the agents: fixed site (one site only) and shifted sites (10 different places). Both cosinor and ANOVA have been used for statistical analyses. The shortest LT (fastest penetration) was located around 04.00h. The longest LT (slowest penetration) occurred during the day with a single peak around 13.00h in three of the situations, or two peaks (HN with fixed site). A rather large rhythm amplitude (peak-to-trough difference larger than 50% of the 24h mean LT) was validated.