Metabolism and pharmacokinetics, in the rat, of (R)-N-(2-Heptyl)Methyl-propargylamine (R-2HMP), a new potent monoamine oxidase inhibitor and antiapoptotic agent.
(R)-N-(2-Heptyl)-N-methylpropargylamine (R-2HMP) is a monoamine oxidase inhibitor and putative antiapoptotic agent analogous to (R)-deprenyl. In the rat, the major amine metabolites of R-2HMP have been identified as (R)-N-2-heptylmethylamine (R-2HMA), (R)-N-2-heptylpropargylamine (R-2HPA), and (R)-2-heptylamine (R-2HA). After R-2HMP was administered s.c. to male Wistar rats, it was observed that the greatest concentration was of the original drug followed in decreasing order by R-2HMA, R-2HPA, and R-2HA in brain, liver, and plasma at all times after administration. The greatest concentrations of the three metabolites were found in brain followed by liver and plasma, and the peak concentrations occurred between 15 and 30 min after administration. After oral administration, the liver contained the greatest concentrations of drug and metabolites, and, again, the peak concentrations occurred at about 15 min. In all cases, depropargylation appears to occur at a faster rate than demethylation. After s.c. administration, R-2HMP and its metabolites exhibited biexponential redistribution and elimination losses. Half-lives of the compounds in brain for the redistribution phase were: R-2HMP, 10 min; R-2HMA, 11 min; R-2HPA, 16 min; and R-2HA, 15 min.
Durden
D A
DA
Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon, Canada. david.durden@usask.ca
Dyck
L E
LE
Davis
B A
BA
Liu
Y D
YD
Boulton
A A
AA
D000284:Administration, Oral; D000465:Algorithms; D000480:Alkynes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D000588:Amines / Q000097:blood / Q000378:metabolism / Q000652:urine; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001711:Biotransformation; D001921:Brain / Q000378:metabolism; D003903:Deuterium; D008401:Gas Chromatography-Mass Spectrometry; D007279:Injections, Subcutaneous; D007553:Isotope Labeling; D008099:Liver / Q000378:metabolism; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000480:Alkynes; D000588:Amines; D008996:Monoamine Oxidase Inhibitors; C402679:N-2-heptyl-N-methylpropargylamine; D003903:Deuterium