Pharmacokinetically guided melatonin scheduling in rats with circadian system suppression.
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 approximately twice as low with continuous light as with LD 12:12. Plasma protein binding of melatonin was approximately 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.
Deprés-Brummer
P
P
Laboratoire Rythmes Biologiques et Chronothérapeutique, ICIG, Villejuif, France.
Metzger
G
G
Morin
D
D
Urien
S
S
Touitou
Y
Y
Tillement
J P
JP
Claustrat
B
B
Lévi
F
F
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001833:Body Temperature Regulation; D002940:Circadian Rhythm; D004334:Drug Administration Schedule; D008297:Male; D008550:Melatonin / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D009043:Motor Activity / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
D001798:Blood Proteins; C054513:6-sulfatoxymelatonin; D008550:Melatonin