Pharmacokinetically guided melatonin scheduling in rats with circadian system suppression

Abstract

To obtain a pharmacologic effect of melatonin in rats kept under prolonged continuous light exposure, conditions known to produce functional suppression of the circadian system, mimicking of the physiologic 24-h pattern of melatonin secretion, a hormonal signal of darkness exposure may be needed. The delivery scheme for melatonin was established in rats in the present studies. First, the plasma pharmacokinetics of [ 3H]melatonin were determined in rats kept under continuous light and in rats synchronized by exposure to alternating 12 h light and 12 h darkness (LD 12:12) in the early light span. The pharmacokinetics of total radioactivity were similar in both groups. Further quantitation of melatonin by thin-layer chromatography revealed differences dependent on light conditions. The mean plasma clearance and steady-state distribution volume were ∼ twice as low with continuous light as with LD 12:12. Plasma protein binding of melatonin was ∼ 33%, irrespective of group or sampling time. These pharmacokinetic parameters were used to devise a 24-h periodic delivery schedule consisting of a 6-h constant infusion of exogenous melatonin, followed by an 18-h melatonin-free interval. In a second study, the melatonin 24-h pattern was estimated from the measurement of 2-h fractions of urinary 6-sulfatoxymelatonin excretion for 4 days. 6 unrestrained rats kept under continuous light received melatonin for 2 days from 22:00 to 04:00 h through an indwelling jugular catheter, connected to a reservoir from a programmable pump. Only the administration of low doses (0.01 mg/kg/day) resulted in both a circadian pattern for 6-sulfatoxymelatonin excretion and normal physiological values during the infusion-free intervals. The resynchronizing efficacy of this schedule should be tested in rats with functional suppression of the circadian system.