The Kinetics of Imipramine‐N‐Oxide in Man

Five healthy volunteers received single doses of imipramine‐N‐oxide (1 mg/kg) by the oral, intramuscular, and intravenous routes. Peak plasma level of imipramine‐N‐oxide was reached one hour after oral administration. The plasma curves of imipramine‐N‐oxide following oral and intravenous administration suggested a monophasic decay with a half‐life ranging between 1.5–2.5 hrs. Pronounced individual differences were observed in the plasma and blood cell concentrations of imipramine‐N‐oxide and the formed metabolites, imipramine and desipramine. The systemic availability of the oral dose of imipramine‐N‐oxide averaged 100 per cent, whereas the systemic availability of the intramuscular injection of imipramine‐N‐oxide averaged 54 per cent. The formation of metabolites was more extensive after intramuscular injection compared with the other routes of administration. The concentration of imipramine‐N‐oxide was lower and the imipramine concentrations higher in blood cells compared to the plasma after all three routes of administration. Thirteen depressed patients received continuous treatment with weekly increasing oral doses of imipramine‐N‐oxide for three weeks and intramuscular injections during the fourth week. They received imipramine during the fifth week. The concentration of imipramine‐N‐oxide and the formed imipramine and desipramine were determined every week both in the plasma and blood cells. The concentration of imipramine and desipramine was lower during treatment with imipramine‐N‐oxide than during treatment with the same dose of imipramine in samples taken 12 hrs after the last dose. In spite of the low concentrations a good clinical effect was noted in the patients investigated. There is a possibility of extensive intracellular formation of imipramine as indicated by the high content of imipramine in the blood cells during the first hours after the administration of imipramine‐N‐oxide.