PLASMA PHARMACOKINETICS, BIOAVAILABILITY, AND TISSUE DISTRIBUTION IN CD2F1 MICE OF HALOMON, AN ANTITUMOR HALOGENATED MONOTERPENE ISOLATED FROM THE RED ALGAE PORTIERIA-HORNEMANNII

The purpose of the present study was to define the plasma pharmacokine tics, bioavailability, and tissue distribution in mice of halomon, a h alogenated monoterpene from Portieria hornemanii that is active in vit ro against brain-, renal-, and colon-cancer cell lines. Halomon formul ated in cremophor:ethanol:0.154 M NaCl (1:1:6, by vol.) was injected i .v. at 20, 60, 90, or 135 mg/kg into female CD2F1 mice. Doses of 135 m g/kg were also given i.p., s.c., and by enteral gavage to female CD2F1 mice and i.v. to male CD2F1 mice. Plasma halomon concentrations were measured with a gas-chromatography system using electron-capture detec tion. Halomon concentrations were also determined in the brains, heart s, lungs, livers, kidneys, spleens, skeletal muscles, fat, red blood c ells, and, if present, testes of mice given 135 mg/kg i.v. Halomon pla sma pharmacokinetics were well fit by a two-compartment, open linear m odel and were linear between 20 and 135 mg/kg. Population estimates of parameters describing halomon plasma pharmacokinetics in female CD2F1 mice were developed with a standard two-stage technique and also by s imultaneous modeling of data from 20-, 60-, 90-, and 135-mg/kg i.v. st udies in female mice. Halomon bioavailability was 45%, 47%, and 4% aft er i.p., s.c., and enteral dosing, respectively. Urinary excretion of the parent compound was minimal. Halomon was distributed widely to all tissues studied but was concentrated and persisted in fat. Halomon co ncentrations measured in the brain were comparable with concomitant co ncentrations detected in plasma and most other tissues. These data and models are helpful in the simulation and evaluation of conditions pro duced by preclinical screening and toxicology studies.