title: Metabolism and pharmacokinetics of N1,N11-diethylnorspermine.
abstract: The pharmacokinetics and metabolism of N1,N11-diethylnorspermine (DENSPM) is described. When administered to dogs as an intravenous bolus, DENSPM was shown to have a plasma half-life of 72.8 +/- 11.8 min, with an early distribution phase half-life of approximately 4 min and an apparent volume of distribution of 0.216 +/- 0.032 liter/kg. The renal clearance half-life was 59.7 +/- 7.6 min, with 48.8 +/- 12.5% of the drug recovered in the urine between 0-4 hr unchanged. In three other experiments, the drug was administered to dogs by constant rate intravenous infusion over periods ranging from 10 min to 2 hr. Analysis of plasma concentration-time data and urinary excretion data yielded pharmacokinetic parameters in general agreement with the intravenous bolus experiments. DENSPM metabolites were identified in both beagle dog and mouse tissues. Tissues were sampled from a single beagle 24 hr posttreatment, and rodent samples were examined at 12, 24, 48, and 96 hr posttreatment. Both the concentration of DENSPM and the metabolic profile were shown to vary in the lung, liver, spleen, and kidney. Although all the tissues examined contained DENSPM and its metabolites, the liver and kidney had the highest level of metabolites that included N1-ethylnorspermine, N1-ethylnorspermidine, N1-ethyl-1,3-diaminopropane, and norspermidine. These data suggest that DENSPM is metabolized by N-deethylation and step-wise removal of aminopropyl equivalents by spermine/spermidine N1-acetyltransferase/polyamine oxidase, a metabolic pathway unique to the polyamines.
authors.affiliation: Department of Medicinal Chemistry, University of Florida, J. Hillis Miller Health Center, Gainesville 32610-0485, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Bergeron
authors.forename: W R
authors.initials: WR
authors.lastname: Weimar
authors.forename: G
authors.initials: G
authors.lastname: Luchetta
authors.forename: R R
authors.initials: RR
authors.lastname: Streiff
authors.forename: J
authors.initials: J
authors.lastname: Wiegand
authors.forename: J
authors.initials: J
authors.lastname: Perrin
authors.forename: K M
authors.initials: KM
authors.lastname: Schreier
authors.forename: C
authors.initials: C
authors.lastname: Porter
authors.forename: G W
authors.initials: GW
authors.lastname: Yao
authors.forename: H
authors.initials: H
authors.lastname: Dimova
mesh_terms: D000818:Animals; D004285:Dogs; D005260:Female; D008297:Male; D051379:Mice; D013096:Spermine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: C059685:N(1),N(11)-diethylnorspermine; D013096:Spermine