To estimate the influence of the digestive tract luminal ammonia pool on acute toxic effects of cyclophosphamide, the dynamics of blood ammonia, glutamine and urea level, symptoms of toxic action and the survival time have been studied in rats, intraperitoneally treated with cyclophosphamide, at the background of the gavage with non-lethal dose of ammonium acetate (12 mmol/kg, i.e., 0.35 LD50). Ammonium acetate enhanced the hyperammonaemic action of cyclophosphamide while promoting its lethal action: the mean survival time decreased 1.5, 2.1, 2.8, or 6.1 times at the background of cyclophosphamide i/p doses 200, 600, 1000, or 1400 mg/kg, respectively. Animals exposed to the combination of toxicants, manifested symptoms which were characteristic of the effect of lethal doses of ammonia salts. These data provide the evidence of the detrimental role of gastrointestinal luminal ammonia in the acute high-dose cyclophosphamide toxicity.
Blood ammonia concentration increased in the portal vein (by 1.4 times) and inferior vena cava (caudal to the renal vein inflow, by 2.2 times; and cranial to the hepatic vein inflow, by 2.5 times) of rats 3 h after intragastric administration of 16.57 M ethanol solution (446 mmol/kg, approximately 1.4 LD(50)/48 h). Ammonia concentration in mixed blood samples (post-decapitation) increased by 39%. The rate of ammonia accumulation was 3-fold higher in an intraperitoneal lavage solution. Three-hour exposure of ethanol-treated animals to atmospheric ammonia (0.84-1.07 mg/liter, i.e. approximately 1/8LC(50) for intact rats) was followed by a 2.4-fold increase in blood ammonia concentration as compared to specimens of the ethanol group. Ammonia inhalation potentiated the lethal effect of ethanol (dose variation factor 0.81), suppressed external respiration, and decreased oxygen consumption. Our results indicate that kinetic changes in endogenous ammonia have an adverse effect on the outcome of alcohol intoxication in rats.
The kinetics of ammonia of gastrointestinal origin has been studied in rats in hematopoietic or neurovascular forms of acute lethal cyclophosphamide intoxication. Portal and caval blood ammonia, glutamine and urea, and blood markers of cytolysis were determined, and transperitoneal ammonia and glutamine fluxes were estimated after the single high-dose cyclophosphamide intraperitoneal (i.p.) administration. Within 3 hours after the administration of cyclophosphamide (200, 600, or 1,000 mg/kg), the portal ammonia level increased 1.4, 1.8, and 2.5 times, respectively; the ammonia level in v. cava caud. caudally of vv. renales inflow increased 1.5, 2.1, and 3.3 times, and cranially of vv. hepaticae, 1.8, 2.7, and 4.2 times, respectively; glutamine:ammonia and urea:ammonia ratios decreased. The rate of ammonia and glutamine accumulation in saline solution injected i.p. exceeded that in control rats dose dependently. At 18 hours after the administration of cyclophosphamide, the increased blood ammonia, glutamine and urea, and glutamine:ammonia ratio persisted. Therefore, in the rat, the high-dose i.p. administration of cyclophosphamide induces the early hyperammonemia, resulting from the enhanced transperitoneal diffusion of gastrointestinal ammonia into the blood, combined with the restriction of glutamine and urea synthesis. These alterations may contribute to neurological complications of myelosuppressive therapeutic regimens of cyclophosphamide administration.
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