METABOLISM AND EXCRETION OF METHYLAMINES IN RATS

Experiments were performed with rats to examine the sources and dispos ition of dimethylamine (DMA), trimethylamine (TMA), and trimethylamine N-oxide (TMAO), all potential substrates for in vivo nitrosation to f orm N-nitrosodimethylamine (NDMA), a potent carcinogen. When bolus dos es of [C-14]DMA or [C-14]TMA were given ip, recovery of radioactivity in the urine was essentially complete, and respiratory excretion, feca l excretion, and accumulation in tissues of these amines or their meta bolites were negligible. Urine analysis following doses of stable isot opes showed that DMA was not converted to TMA or TMAO. Varying amounts of TMA were oxidized to TMAO, the fraction oxidized decreasing at hig her doses of TMA. Ingestion and excretion of naturally occurring methy lamines were monitored over a 5-day period in separate groups of norma l and germ-free rats. The results of these metabolic balance studies i ndicate that there is net synthesis of DMA by gut bacteria and net con sumption of TMAO by endogenous processes. The net intake or excretion of TMA and TMAO observed in normal and germ-free rats is consistent wi th bacterial synthesis of TMA followed by its almost complete oxidatio n to TMAO. Blood concentrations of DMA and TMA were measured in rats f or 8 hr following <5, 100, or 1000 mu mol bolus iv or ip doses of radi oisotopes or stable isotopes. At any given dose of DMA or TMA, the dec ay in blood concentration was approximately monoexponential. At the lo west (most physiologic) dose the apparent volume of distribution (V-D) for DMA was larger than that for TMA. Both values of V-D greatly exce eded the size of the animals, suggesting that DMA and TMA are highly c oncentrated at one or more locations in the body. This was confirmed b y measurements in tissue homogenates sampled 1 hr after a dose. The ov erall handling of methylamines by rats is generally consistent with ob servations in humans. The presence of high local concentrations of DMA and TMA at various extragastric sites merits further investigation in connection with the potential for endogenous nitrosation of these met hylamines to form NDMA. (C) 1994 Academic Press, Inc.