Cyclophosphamide-induced leakage of gastrointestinal ammonia into the common bloodstream in rats

Abstract

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.

Secondary Dysfunction of the Intestinal Barrier in the Pathogenesis of Complications of Acute Poisoning

“…This process, transperitoneal diffusion, is facilitated by the absence of the large-intestinal diffusion barrier in the form of a continuous longitudinal muscular layer [ 13 ]. Transperitoneal diffusion of ammonia [ 14 ] and endotoxin has been shown experimentally [ 15 ]. The substances involved in transperitoneal diffusion avoid presystemic metabolism in the liver on their way to the general blood flow.…”

“…From the intestinal chyme, ammonia enters the general blood flow through both the portal vein and the liver, as well as via transperitoneal diffusion [ 14 ]. In a healthy individual, about 4 g of ammonia is delivered into blood (mainly portal) from the intestine daily [ 31 ].…”