The concomitant administration of diazepam and imipramine hydrochloride increased desipramine concentration in rat plasma, but decreased 2-hydroxyimipramine and 2-hydroxydesipramine concentrations; the concomitant administration of oxazepam and imipramine hydrochloride decreased imipramine, 2-hydroxyimipramine, and 2-hydroxydesipramine concentrations. lmipramine plasma protein binding was unaltered in all cases. Liver concentrations of imipramine and 2hydroxydesipramine were increased by concomitant administration of oxazepam and imipramine hydrochloride. Concomitant administration of benzodiazepines and imipramine hydrochloride increased imipramine concentration in the brain. The effects of imipramine hydrochloride on hypothermia induced by reserpine, and on behavioral despair in rats was also studied. The concomitant administration of diazepam and imipramine hydrochloride led to a decrease in the anti-reserpine effect of imipramine hydrochloride and in the irnipramine hydrochloride-induced recovery from immobility in the forced swimming test. These results are in accord with the findings on brain concentrations of imipramine and its metabolites.
For the medical treatment of depression and neurosis, the concomitant administration o f tricyclic antidepressants and benzodiazepines i s widely used. There are various reports w i t h regard to this concomitant use. Silverman and Braithwaitel reported that, because the concomitant use of these drugs h a d no effect o n the drug metabolizing system, interaction of these drugs presented no serious problem. However, Fann and Wheless2 reported that n o t only was the concomit a n t use of these drugs better than monotreatment w i t h each drug for medical treatment, but t h a t these drugs showed supernumerary sedative action. Furthermore, Ban3 reported t h a t the concomitant use of these drugs may aggravate depression. These reports suggest the existence of an interaction between tricyclic antidepressants and benzodiazepines. In our previous studies,G7 we showed t h a t concomitant administration of imipramine hydrochloride and benzodiazepines to rats does result in drug interaction: the plasma concentration and metabolism of imipramine and diazepam were modified by the concomitant use of imipramine hydrochloride and diazepam, and the pharmacodynamics of diazepam was enhanced by the concomitant use o f imipramine hydrochloride. In the present study, we investigated the effect of benzodiazepines on the pharmacokinetics and pharmacodynamics o f imipramine hydrochloride.
Experimental Section
Animals and Drugs-Adult male Sprague-Dawley rats (Charles River Japan, Inc.; body weight 250 2 10 g) were used in all experiments. The animals were housed in groups of five in wire-mesh cages of the following dimensions: 26(width) x 18(height) x 38(depth) em. Rats were given laboratory chow (MF, Oriental Yeast Co., Tokyo) and tap water ad libitum under a 12-h light-dark cycle, but were deprived of food for 18 h prior to the experiments. The room temperature was kept a t 23 _t 0.5 "C, and the humidity was 55 ? 5%.
In the in vivo studies, imipramine hydrochloride (5-[3-(dimethylamino)propyl]-10,l l-dihydro-!iH-dihenz[ b,flazepine monohydrochloride; Ciba-Geigy Japan, Inc., 20 or 50 mg/mL/kg) was dissolved in a 1% aqueous solution of carboxymethyl cellulose (CMC, Wako Pure Chemical Co., Ltd.). Diazepam (7-chloro-l,3-dihydro-l-methyl-5phenyl-2H-1,4-benzodiazepin-2-one; Nippon Roche, Inc., 5 mglmlikg) and oxazepam (7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-W-1,4-benzodiazepin-2-one; Nippon Roche, Inc., 20 mg/mL/kg) were also suspended in a 1% aqueous solution of CMC. In the in vitro 56