Imipramine and desipramine disposition in the elderly

Forty-six healthy male and female volunteers aged 21 to 88 received single 12.5-mg i.v. doses of imipramine, and 35 of these people received single 50-mg p.o. imipramine doses on a different occasion. Thirty-five similar volunteers received single 50-mg p.o. desipramine doses. Among these subjects 25 participated in studies of both imipramine and desipramine. Kinetic variables for the respective drugs were determined from multiple plasma drug concentrations from samples obtained during 96 hr after the dosage. Imipramine half-life was markedly prolonged in elderly vs. young males (28.6 vs. 16.5 hr; P < .001) and females (30.2 vs. 17.8 hr; P < .01) due to decreased clearance (males: 567 vs. 945 ml/min, P < .01; females: 599 vs. 975 ml/min, P < .005) with no change in volume of distribution. After p.o. imipramine doses time to peak imipramine concentration was shorter in elderly females (2.1 vs. 4.8 hr; P < .005) but no different in males. Peak concentration achieved was greater in the elderly of both sexes (males: 40.2 vs. 19.5 ng/ml, P < .005; females: 44.7 vs. 10.4 ng/ml, P < .01). Comparison of p.o. and i.v. imipramine doses indicated no difference in absolute bioavailability between the elderly and young of either sex. In contrast, after p.o. desipramine more limited age-related changes were noted. Desipramine half-life was slightly prolonged in elderly males (30.8 vs. 21.2 hr; P < .05) apparently related to a nonsignificant decrease in p.o. clearance. No difference in desipramine half-life or p.o. clearance was noted in elderly vs. young females. Peak plasma desipramine concentration achieved was not related to age for either sex; however, time to peak concentration was slightly prolonged in elderly males (8.9 vs. 5.2 hr; P < .02). Plasma protein binding of both imipramine and desipramine was not related to age or sex. Therefore, clearance of the tertiary amine imipramine, which is predominantly biotransformed by demethylation, may be more sensitive to effects of age than desipramine, for which the major biotransformation pathway is hydroxylation.