ISSN:
1432-0843
Keywords:
Key words BE-4-4-4-4
;
Polymines
;
Pharmacokinetics
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract 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, ∼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 μg/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 μM) in mouse plasma was approximately 67% protein-bound. Bioavailabilities 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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/s002800050441
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