Deuterium isotope effect on the toxicokinetics of monomethylamine in the rat.
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 mumol/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.
Streeter
A J
AJ
Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick, MD 21701.
Nims
R W
RW
Sheffels
P R
PR
Hrabie
J A
JA
Ohannesian
L
L
Heur
Y H
YH
Mico
B A
BA
Keefer
L K
LK
D000818:Animals; D001682:Biological Availability; D003903:Deuterium; D006207:Half-Life; D066298:In Vitro Techniques; D008297:Male; D008744:Methylamines / Q000493:pharmacokinetics / Q000633:toxicity* / Q000652:urine; D008782:Methylurea Compounds / Q000493:pharmacokinetics / Q000633:toxicity / Q000652:urine; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344
D008744:Methylamines; D008782:Methylurea Compounds; D003903:Deuterium; C027451:methylamine; C002352:methylurea