title: Time-of-day dependent pharmacodynamic and pharmacokinetic profiles of caffeine in rats.
abstract: This study aims to investigate the effects of caffeine on the daily rhythms of heart rate (HR), body temperature (BT) and locomotor activity (LA) in rats in relation to time-of-day of administration, as well as their possible mechanisms, particularly related to caffeine pharmacokinetics. During the pharmacodynamic study, HR, BT and LA were measured every 10 min by radiotelemetry and analysed by Cosinor. This study was divided into three periods: a control period P1, a treatment period P2 and a recovery period P3. During P2, rats of the morning group ( M(tel)) received a 25 mg/kg s.c. dose of caffeine at 08.00 while rats of the evening group ( E(tel)) received the same dose of caffeine at 20.00. The pharmacokinetic study was conducted in parallel with the telemetric study and was divided into two periods: a control period P1, and a treatment period P2. During P2, animals of the morning ( M(pk)) and the evening ( E(pk)) groups received the same treatment as the animals of the telemetric study. At the last day of P2, blood samples were drawn 0.25, 0.5, 1, 2, 4, 8, 12 and 24 h after the last morning and the last evening administration in order to determine the pharmacokinetics of M(pk) and E(pk). Our results showed that morning administration of caffeine suppressed the daily rhythmicity of LA and modified the mesors and amplitudes of the HR and BT daily rhythms, while the evening administration did not suppress the daily rhythm of LA, but altered the mesors, amplitudes and acrophases of the three rhythms, indicating a chronopharmacological effect. With respect to the pharmacokinetic effects, the area under the curve (AUC) was significantly lower in rats of E(pk) compared with M(pk), due to an increase of the total plasma clearance and the volume of distribution. Our data suggest that the chronopharmacokinetic effects of caffeine may explain, at least in part, the observed caffeine-induced modifications on the daily rhythms.
authors.affiliation: Laboratoire de Pharmacologie Médicale et Clinique, Faculté de Médecine, Université de la Méditerranée, 27 Bd. Jean Moulin, 13385 Marseille Cedex 5, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Pelissier-Alicot
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schreiber-Deturmeny
authors.forename: Nicolas
authors.initials: N
authors.lastname: Simon
authors.forename: Manon
authors.initials: M
authors.lastname: Gantenbein
authors.forename: Bernard
authors.initials: B
authors.lastname: Bruguerolle
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D002110:Caffeine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002940:Circadian Rhythm; D006339:Heart Rate / Q000187:drug effects*; D007279:Injections, Subcutaneous; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013686:Telemetry
chemical_list: D000697:Central Nervous System Stimulants; D002110:Caffeine