Abstract

The pharmacokinetics and metabolism of N1,N14-diethylhomospermine (DEHSPM) is described. Analysis of 15 min constant rate intravenous infusion data in dogs gave mean values of: plasma t1/2 = 1.04 hr; Vd = 0.514 liter/kg; CL = 0.343 liter/hr/kg; and AUC0-infinity = 43.2 mg/hr/liter. The renal t1/2 = 0.99 hr, with 36% of the drug recovered in the urine between 0-4 hr unchanged. In other experiments, the drug was administered to dogs by subcutaneous injection. Noncompartmental analysis of plasma concentration-time data showed a mean residence time (MRT) of 4.67 hr (subcutaneous) vs. 1.93 hr (intravenous). Mice and dogs received DEHSPM chronically to evaluate tissue distribution of DEHSPM and its metabolites. All tissues examined contained DEHSPM and its N-deethylated metabolites, N1-ethylhomospermine (MEHSPM) and homospermine (HSPM). On day 1 posttreatment, 35% of the total dose administered to mice was present in the liver (25%) and kidney (10%). The DEHSPM present declines rapidly (liver t1/2 = 1.6 days). The majority of the original dose was present as HSPM, which persisted in tissues for weeks (liver t1/2 = 15.4 days). These data suggest that DEHSPM and MEHSPM are metabolized by N-deethylation, but that HSPM is not susceptible to further degradation by polyamine catabolic enzymes that involves stepwise removal of aminopropyl equivalents by spermine/spermidine N1-acetyltransferase/polyamine oxidase. Thus, chronic DEHSPM dosing regimens in both dogs and mice may result in the accumulation of HSPM, which is retained by tissues for an extended period of time resulting in disruption of normal polyamine homeostasis in these tissues. These findings correlate with clinical and histopathological signs of toxicity in dogs and in mice.