Deuterium isotope effect on the toxicokinetics of monomethylamine in the rat
Streeter, A.J.; Nims, R.W.; Sheffels, P.R.; Hrabie, J.A.; Ohannesian, L.; Heur, Y.H.; Mico, B.A.; Keefer, L.K.
Drug Metabolism and Disposition the Biological Fate of Chemicals 18(4): 447-452
1990
ISSN/ISBN: 0090-9556 PMID: 1976066 Document Number: 645
The single-dose toxicokinetics of monomethylamine has been characterized in the rat by HPLC assay of serial blood samples. Biphasic first-order elimination was observed following an iv bolus dose of 19 .mu.mol/kg with a terminal half-life of 19.1 .+-. 1.3 min (mean .+-. SE, N = 4). The apparent steady state volume of distribution, systemic blood clearance, and renal blood clearance were 1.21 .+-. 0.09 liter/kg, 53.4 .+-. 3.5 ml/min/kg, and 5.72 .+-. 0.53 ml/min/kg, respectively. The administration of an intragastric dose permitted the calculation of the systemic bioavailability of monomethylamine as 69 .+-. 3%. Duplicate experiments using the structural analogue with deuterium atoms substituted for hydrogens on the methyl group revealed a much slower elimination of the compound, although ultimately, 5 times as much was excreted unchanged in the urine. Isotope effects calculated as the ratios of terminal half-life, systemic blood clearance, and systemic bioavailability were 1.9, 2.2, and 1.8, respectively.
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