Chronobiological variations of indomethacin pharmacokinetic parameters in sheep

A two-phase study to investigate the influence of administration time on ph armacokinetics of indomethacin in sheep was performed. In phase I, 12 anima ls were allocated to four groups, each corresponding to a different time: 0 8:00, 14:00, 20:00, 02:00 h. Sheep received an intravenous administration o f 1 mg/kg indomethacin. In phase II, each group was administered indomethac in with a 12-h difference compared to Phase I. The trial was performed in a utumn, and animals were subjected to a natural light:dark cycle of 10:14 h. Blood samples were taken and processed by high performance liquid chromato graphy (HPLC) with ultraviolet detection. For each pharmacokinetic paramete r, an analysis of variance was performed to outline the existence of chrono biological variations. Concentration at zero time (C-0), hybrid constant fo r distribution and its half life, hybrid constant for elimination and its h alf-life, volume of distribution ( V-d), area under the curve (AUC(infinity )) and clearance rate (CI), presented chronobiological variations (P < 0.05 ) and were fitted to a cosine equation. The following parameters adjusted t o circadian rhythms: C-0 (acrophase: 13.9788 h); AUC(infinity) (acrophase: 13.4377 h); V-d (acrophase: 0.8245 h) and Cl (acrophase: 1.4965 h), It was concluded that pharmacokinetic parameters of intravenously injected indomet hacin in sheep would behave in a different, though predictable, manner acco rding to the animal's biological clock.