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ABSTRACT: The effects of daily oral administration of imipramine hydrochloride (5-[3-(dimethylamino)propyl]-10, 11 -dihydro-5H-dibenz-[b,f]azepine monohydrochloride; 50 mg/kg) and/or diazepam (7-chloro-1, 3-dihydro-1 -methyl-5-phenyl-2H-1, 4-benzodiazepin-2-one; 5 mg/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 (5 mg/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 100 g 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 (5 mg/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 (5 mg/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.
Journal of Pharmaceutical Sciences 09/2006; 75(11):1071 - 1075. · 3.06 Impact Factor
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ABSTRACT: 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. Imipramine plasma protein binding was unaltered in all cases. Liver concentrations of imipramine and 2-hydroxydesipramine 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 imipramine 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.
Journal of Pharmaceutical Sciences 09/2006; 77(1):56 - 63. · 3.06 Impact Factor
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ABSTRACT: A comparative study of the effect of misonidazole and novel radiosensitizers on glutathione (GSH) levels and related enzyme activities in isolated rat hepatocytes was performed. Incubation of hepatocytes with 5 mM radiosensitizers led to a decrease in the intracellular GSH level. The most pronounced decrease in cellular GSH was evoked by 2,4-dinitroimidazole-1-ethanol (DNIE); after incubation for only 15 min, GSH was hardly detected. DNIE-mediated GSH loss was dependent upon its concentration. DNIE reacted with GSH nonenzymatically as well as with diethylmaleate, while misonidazole and 1-methyl-2-methyl- sulfinyl-5-methoxycarbonylimidazole (KIH-3) did not. Addition of partially purified glutathione S-transferase (GST) did not enhance DNIE-mediated GSH loss in a cell-free system. DNIE inhibited glutathione peroxidase (GSH-Px), GST, and glutathione reductase (GSSG-R) activities in hepatocytes, while misonidazole and KIH-3 did not. GSH-Px activity assayed with H2O2 as substrate was the most inhibited. Inhibition of GSH-Px activity assayed with cumene hydroperoxide as substrate and GST was less than that of GSH-Px assayed with H2O2 as substrate. GSSG-R activity was decreased by DNIE, but not significantly. Incubation of purified GSH-Px with DNIE resulted in a little change in the activity when assayed with H2O2 as substrate.
Life Sciences 09/1985; 37(7):625-633. · 2.53 Impact Factor
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ABSTRACT: Age and sex differences in the hepatic glutathione level and related enzyme activities in rats of both sexes were investigated. At 7 weeks of age there was no significant difference in GSH levels between males and females, although a higher level of intracellular GSH was observed in male rats at 12 weeks of age. Hepatic γ-glutamyl transpeptidase activities were significantly higher in females than in males at only 7 weeks of age. Glutathione peroxidase showed higher activities in females than in males. Conversely, glutathione S -transferase, glutathione reductase and glutathione synthesis rates were markedly higher in males than in females.
Journal of Biochemistry 02/1983; · 2.37 Impact Factor
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ABSTRACT: Changes in the activity of gamma-glutamyltranspeptidase (GGT, EC 2.3.2.2) during development in rats were investigated. The activity of GGT in fetal liver increased rapidly immediately before birth, reached a maximum at birth and then decreased rapidly within a week after birth to nearly the level in adult rat liver. In contrast, placental GGT showed higher activity at an early stage (from day 13 to day 15) of the gestation period, but the activity decreased in the last part of fetal life. The activity in the amniotic fluid increased significantly just before birth, in parallel with the increase of activity in the fetal liver. No change of activity in the uterine wall was observed throughout gestation. The kinetic and immunological properties of partially purified GGTs from fetal liver and placenta were almost identical with those of adult liver GGT. However, the activity of soluble GGT in fetal liver was less effectively inhibited by antibody against adult kidney GGT. Thus, it is likely that at least one isozyme of GGT is present in the soluble fraction of fetal liver.
Life Sciences 09/1981; · 2.53 Impact Factor
