PLASMA PHARMACOKINETICS AND URINARY-EXCRETION OF THE POLYAMINEANALOGUE 1,19-BIS(ETHYLAMINO)-5,10,15-TRIAZANONADECANE IN CD2F1 MICE

The pharmacokinetics of 1, 19-bis(ethylamino)-5, 10, 15-triazanonadeca ne (BE-4-4-4-4) were determined in CD2F1 female mice after administrat ion of i.v. bolus doses of 20 mg/kg (approximately the dose lethal to 10% of the study animals, similar to LD(50)) 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 p lasma and urine was derivatized with dansyl chloride and measured by g radient high-performance liquid chromatography (HPLC) with fluorescenc e detection. Data were modeled by noncompartmental and compartmental m ethods. The declines observed in plasma BE-4-4-4-4 concentrations afte r 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 approximate d 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. do se of 20 mg/kg ranged between 30 and 33 mu g/ml, the terminal eliminat ion half-life was 94 min, and the volume of distribution (V-dss) was 8 50 ml/kg. The plasma pharmacokinetics of BE-4-4-4-4 were linear with d ose. BE-4-4-4-4 (0.5 and 2.0 mu M) in mouse plasma was approximately 6 7% protein-bound. Bioavailabilities after i.p., s.c., and p.o. deliver y 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 les s than 30% of the delivered dose, As BE-4-4-4-4 proceeds toward and un dergoes clinical evaluation, the data and analytical method presented herein should prove useful in formulating a dose-escalation strategy a nd, possibly, evaluating toxicities encountered.