Metabolism and excretion of methylamines in rats.
Experiments were performed with rats to examine the sources and disposition of dimethylamine (DMA), trimethylamine (TMA), and trimethylamine N-oxide (TMAO), all potential substrates for in vivo nitrosation to form N-nitrosodimethylamine (NDMA), a potent carcinogen. When bolus doses of [14C]DMA or [14C]TMA were given ip, recovery of radioactivity in the urine was essentially complete, and respiratory excretion, fecal excretion, and accumulation in tissues of these amines or their metabolites were negligible. Urine analysis following doses of stable isotopes showed that DMA was not converted to TMA or TMAO. Varying amounts of TMA were oxidized to TMAO, the fraction oxidized decreasing at higher doses of TMA. Ingestion and excretion of naturally occurring methylamines were monitored over a 5-day period in separate groups of normal and germ-free rats. The results of these metabolic balance studies indicate that there is net synthesis of DMA by gut bacteria and net consumption of TMAO by endogenous processes. The net intake or excretion of TMA and TMAO observed in normal and germ-free rats is consistent with bacterial synthesis of TMA followed by its almost complete oxidation to TMAO. Blood concentrations of DMA and TMA were measured in rats for 8 hr following < 5, 100, or 1000 mumol bolus i.v. or ip doses of radioisotopes or stable isotopes. At any given dose of DMA or TMA, the decay in blood concentration was approximately monoexponential. At the lowest (most physiologic) dose the apparent volume of distribution (VD) for DMA was larger than that for TMA. Both values of VD greatly exceeded the size of the animals, suggesting that DMA and TMA are highly concentrated at one or more locations in the body. This was confirmed by measurements in tissue homogenates sampled 1 hr after a dose. The overall handling of methylamines by rats is generally consistent with observations 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 methylamines to form NDMA.
Smith
J L
JL
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge 02139.
Wishnok
J S
JS
Deen
W M
WM
D000818:Animals; D002250:Carbon Radioisotopes; D004123:Dimethylamines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D004128:Dimethylnitrosamine / Q000378:metabolism / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D008401:Gas Chromatography-Mass Spectrometry; D008297:Male; D008744:Methylamines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D012588:Scintillation Counting
D002250:Carbon Radioisotopes; D004123:Dimethylamines; D008744:Methylamines; C034516:dimethylamine; C005855:trimethyloxamine; C023336:trimethylamine; D004128:Dimethylnitrosamine