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Chronopharmacokinetics of indomethacin in rats.

In order to establish the origin of the circadian variations in the kinetics of indomethacin (Indocid) observed in humans, a chronopharmacokinetic study was developed in rats. In a first experiment, 3 groups of 24 h fasted rats each received a single i.v. dose of 0.25 or 0.5 or 1 mg/kg b.w. of indomethacin, respectively, at 8 h. Thus it could be demonstrated that the pharmacokinetics of indomethacin were linear in the dose range studied and obeyed a two-compartment model. In a second experiment, 3 other groups of rats from same strain received a single i.v. dose of 0.5 mg/kg b.w. of indomethacin at 2 h, 14 h and 20 h, respectively. In the 4 groups of rats having received 0.5 mg/kg b.w. of indomethacin, it was observed that only the pharmacokinetic parameters which reflected the distribution process exhibited significant circadian variations. When the animals were dosed at 2 h (physiological rest time for rats) the initial plasma concentration (Co = 4.2 +/- 0.08 micrograms/ml) and the area under the curve (AUC = 13.6 +/- 0.5 h micrograms/ml) was significantly lower while the distribution volume (Vd/b.w. = 120 +/- 2 ml/kg) and the total metabolic clearance (ClT/b.w. = 25 +/- 1.1 ml/h/kg) were higher than those observed in rats dosed at 20 h (period of activity). The apparent elimination half-life was not significantly altered by the time of administration. These results are in good agreement with those that we have previously reported in humans orally dosed with indomethacin, and suggest that the mechanisms of the circadian changes of the pharmacokinetics of indomethacin are mainly related to alterations in the drug distribution.