Plasma pharmacokinetics and urinary excretion of the polyamine analogue 1, 19-bis(ethylamino)-5, 10, 15-triazanonadecane in CD2F1 mice.
The pharmacokinetics of 1, 19-bis(ethylamino)-5, 10, 15-triazanonadecane (BE-4-4-4-4) were determined in CD2F1 female mice after administration of i.v. bolus doses of 20 mg/kg (approximately the dose lethal to 10% of the study animals, approximately LD10) as well as 15, 10, and 5 mg/kg and after s.c., i.p., or p.o. doses of 20 mg/kg. BE-4-4-4-4 in plasma and urine was derivatized with dansyl chloride and measured by gradient high-performance liquid chromatography (HPLC) with fluorescence detection. Data were modeled by noncompartmental and compartmental methods. The declines observed in plasma BE-4-4-4-4 concentrations after i.v. delivery of 20, 15, 10, and 5 mg/kg were modeled simultaneously using an interval of 2000 min between doses and were best approximated by a two-compartment, open, linear model. The time courses of plasma BE-4-4-4-4 concentrations after i.p. and s.c. delivery were fit best by a two-compartment, open, linear model with first-order absorption. Peak plasma concentrations of BE-4-4-4-4 measured following an i.v. dose of 20 mg/kg ranged between 30 and 33 microgram/ml, the terminal elimination half-life was 94 min, and the volume of distribution (Vdss) was 850 ml/kg. The plasma pharmacokinetics of BE-4-4-4-4 were linear with dose. BE-4-4-4-4 (0.5 and 2.0 microM) in mouse plasma was approximately 67% protein-bound. Bio-availabilities after i.p., s.c., and p.o. delivery were 40%, 50%, and approximately 3%, respectively. Urinary excretion of parent BE-4-4-4-4 in the first 24 h after dosing accounted for less than 30% of the delivered dose. As BE-4-4-4-4 proceeds toward and undergoes clinical evaluation, the data and analytical method presented herein should prove useful in formulating a dose-escalation strategy and, possibly, evaluating toxicities encountered.
Eiseman
J L
JL
Division of Developmental Therapeutics, University of Maryland Cancer Center, Baltimore, MD 21201, USA.
Yuan
Z M
ZM
Eddington
N D
ND
Sentz
D L
DL
Callery
P S
PS
Egorin
M J
MJ
D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006207:Half-Life; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D016014:Linear Models; D008297:Male; D051379:Mice; D011485:Protein Binding; D013047:Specific Pathogen-Free Organisms; D013096:Spermine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine
D000970:Antineoplastic Agents; D001798:Blood Proteins; C082768:BE 4-4-4-4; D013096:Spermine