Metabolism and pharmacokinetics of N1,N11-diethylnorspermine in a Cebus apella primate model.
The tissue distribution, metabolic profile, and pharmacokinetic parameters of i.v.-administered N1,N11-diethylnorspermine (DENSPM) are evaluated in Cebus apella primates, and the results are compared with data gathered from canine and human studies. Although the metabolic processing of DENSPM (i.e., deethylation and deaminopropylation) in dogs and primates is very similar, there are some significant differences in tissue distribution of the parent drug. In dogs, the organ concentration of DENSPM follows the order kidney >> liver approximately = lung > spleen. In the primate, the order is liver >> kidney approximately = spleen > lung. The difference in pharmacokinetic parameters between the species is profound with (area under the time-concentration curve)primate << (area under the time-concentration curve)dog; (terminal elimination half-life)primate << (terminal elimination half-life)dog; and (mean residence time)primate << (mean residence time)dog. The most notable difference between dogs and primates is seen in the fraction of parent drug excreted unchanged in the urine, 50% in the dog and < 1% in the primate. However, the pharmacokinetic parameters and urinary drug clearance in C. apella primates are remarkably similar to those in humans. Thus, C. apella is established as an excellent model for assessing the metabolism, tissue distribution, and pharmacokinetic properties of polyamine analogues.
Bergeron
R J
RJ
Department of Medicinal Chemistry, University of Florida, Gainesville 32610, USA. bergeron@mc.cop.ufl.edu
Merriman
R L
RL
Olson
S G
SG
Wiegand
J
J
Bender
J
J
Streiff
R R
RR
Weimar
W R
WR
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine*; D002428:Cebus / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D013045:Species Specificity; D013096:Spermine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D014018:Tissue Distribution
D000970:Antineoplastic Agents; C059685:N(1),N(11)-diethylnorspermine; D013096:Spermine