PHARMACOKINETICALLY GUIDED MELATONIN SCHEDULING IN RATS WITH CIRCADIAN SYSTEM SUPPRESSION

To obtain a pharmacologic effect of melatonin in rats kept under prolo nged 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 exposu re may be needed. The delivery scheme for melatonin was established in rats in the present studies. First, the plasma pharmacokinetics of [H -3]melatonin were determined in rats kept under continuous light and i n rats synchronized by exposure to alternating 12 h light and 12 h dar kness (LD 12:12) in the early light span. The pharmacokinetics of tota l radioactivity were similar in both groups, Further quantitation of m elatonin by thin-layer chromatography revealed differences dependent o n light conditions. The mean plasma clearance and steady-state distrib ution volume were similar to twice as low with continuous light as wit h LD 12:12. Plasma protein binding of melatonin was similar to 33%, ir respective 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 mel atonin-free interval. In a second study, the melatonin 24-h pattern wa s estimated from the measurement of 2-h fractions of urinary 6-sulfato xymelatonin excretion for 4 days. 6 unrestrained rats kept under conti nuous light received melatonin for 2 days from 22:00 to 04:00 h throug h an indwelling jugular catheter, connected to a reservoir from a prog rammable pump. Only the administration of low doses (0.01 mg/kg/day) r esulted in both a circadian pattern for 6-sulfatoxymelatonin excretion and normal physiological values during the infusion-free intervals. T he resynchronizing efficacy of this schedule should be tested in rats with functional suppression of the circadian system.