Abstract
Inhibition of barbiturate metabolisms by imipramine (IP) was studied systematically in the in vitro system and intact rats with an emphasis on the contribution of metabolism of the inhibitor itself. Both IP and its major metabolite, desmethylimipramine (DMI) were found to inhibit the in vitro microsomal metabolisms of various barbiturates. The time courses of the inhibitory activities of IP and DMI were also studied in the intact animals. The maximum inhibition was observed at approximately 3 hours after the administration of both IP and DMI and the significant inhibition was observed for further about 10 hours. Hexobarbital hypnosis as a pharmacological action was similarly affected by IP administration. The possible participation of the metabolite DMI was confirmed by studying the effect of preincubation of IP in the in vitro system and determining directly the levels of IP and DMI in the liver tissue at various times after IP administration. The effect of dose and long-term pretreatment of IP on the microsomal metabolism of barbiturates was examined and the dispositions of IP were found to be of linear nature. Species differences in the in vitro metabolic inhibition by IP were also examined. And furthermore, as a measure of the physiological availabilities of IP and DMI, lipid solubility, ionization constant, and absorption from the rat small intestine were discussed in connection with the inhibitory mechanism of IP.
