Effects of Combined Administration of Diazepam and Imipramine Hydrochloride in Rats

Abstract

The effects of daily oral administration of imipramine hydrochloride (5-[3-(dimethylamino)propyl]-10, 11 -dihydro-5H-dibenz-[b,f]azepine monohydrochloride; 50mg/kg) and/or diazepam (7-chloro-1, 3-dihydro-1 -methyl-5-phenyl-2H-1, 4-benzodiazepin-2-one; 5mg/kg) in a 1% aqueous solution of carboxymethylcellulose sodium salt (CMC) on the body weight, organ weights, and activities of various enzymes, including drug metabolizing enzyme systems were investigated in rats during a 15-day period. The plasma concentrations of imipramine and desipramine were also determined. In addition, the effect of a single intravenous administration of imipramine hydrochloride (5mg/kg) on the plasma concentration-time profiles of imipramine and desipramine was investigated in rats given the same drug treatments. The plasma concentration-time profiles of imipramine and desipramine were analyzed pharmacokinetically. The rats treated with imipramine hydrochloride showed a greater inhibition of body weight gain than those treated with diazepam, and those treated with imipramine hydrochloride and diazepam simultaneously showed a body weight gain similar to those treated with imipramine hydrochloride alone. No significant differences in organ weight (per 100g of body weight) were found. The imipramine hydrochloride plus diazepam treatment group showed a greater increase in drug-metabolizing enzyme activities than the imipramine hydrochloride treatment group, but the difference was not statistically significant. However, the plasma levels of imipramine and desipramine after oral administration for 15 d suggested that the imipramine hydro-chloride plus diazepam treatment group did show increased imipramine metabolism. Single intravenous administration of imipramine hydrochloride caused a reduction in the first-order elimination rate constant (kel) in the imipramine hydrochloride treatment group, and reductions of the first-order distribution rate constants (k12, k21) and kel in the imipramine hydrochloride plus diazepam treatment group. In terms of the area under the concentration-time curve (AUC) of desipramine after intravenous administration of imipramine hydrochloride (5mg/kg), there was no significant difference between the imipramine hydrochloride treatment group and the imipramine hydrochloride plus diazepam treatment group. Plasma desipramine was not detectable after intravenous administration of imipramine hydrochloride (5mg/kg) to the control group. The results indicate that daily oral administration of imipramine hydrochloride enhances the metabolism of imipramine and may induce changes of distribution and excretion of imipramine and desipramine. The effects appear to be greater in the case of coadministration of imipramine hydrochloride and diazepam.