Pharmacokinetic patterns of repeated administration of antidepressants in animals. I. Implications for antinociceptive action of clomipramine in mice.

The pattern of repeated administration of antidepressants in animals varies from one study to another, making comparison of results difficult. We propose a means of standardizing the pattern of administration for any particular animal, based on a pharmacokinetic study of the antidepressant [here clomipramine (CMI)] in that animal. The plasma half-life (127 min) in the Swiss CD1 mouse was used as a basis for chronic administration, which was strictly every half-life as in clinical use. Daily administration is thus merely repeated acute administration. The antinociceptive action of CMI was compared under four sets of conditions of injection: single, chronic, daily and closely repeated (every 40 min). The antinociceptive effect obtained after an acute injection of CMI (10 or 20 mg/kg i.p.) was increased 2-fold after five chronic injections. Closely repeated injections gave a more marked effect than chronic administration, and daily administration was ineffective. The time course of the antinociceptive action correlated with that of blood and brain levels of CMI and its monodemethylated derivative. The enhancement of the antinociceptive action observed after chronic and closely repeated administration was shown not to be due to any modification of motor activity. It was suppressed by naloxone. Comparison with results reported in the literature shows the benefit of using a well-defined pattern of administration.