Absorption and disposition of 2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2-methylpropanoic acid, WIN 35,833, in rats, monkeys, and men.
2-[4-(2,2-Dichlorocyclopropyl)phenoxy]-2-methylpropanoic acid, Win 35,833, was readily absorbed after oral administration; in rats, rhesus monkeys, and human volunteers, peak concentrations of drug in plasma were attained within 2 hr of medication. The time-concentration curve of administered drug was biphasic in monkeys and men, while in rats the kinetics of a one-compartment model were observed. Distribution studies of 14C-labeled drug in the rat showed that most of the radioactivity was excreted in the feces and that significant quantities of 14C were sequestered by depot fat. Monkeys and human subjects both eliminated Win 35,833 primarily through the kidneys. The drug was excreted in rat bile and human urine, both as the free acid and conjugated with glucuronic acid. At physiological concentrations, Win 35,833 was extensively bound to rat, monkey, and human plasma proteins. A gas-chromatographic method for the analysis of drug in plasma, urine, or bile gave a linear relationship between peak height ratios and concentrations, in the range of 1-60 mug/ml.
Absorption and disposition of 2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2-methylpropanoic acid, WIN 35,833, in rats, monkeys, and men. 2-[4-(2,2-Dichlorocyclopropyl)phenoxy]-2-methylpropanoic acid, Win 35,833, was readily absorbed after oral administration; in rats, rhesus monkeys, and human volunteers, peak concentrations of drug in plasma were attained within 2 hr of medication. The time-concentration curve of administered drug was biphasic in monkeys and men, while in rats the kinetics of a one-compartment model were observed. Distribution studies of 14C-labeled drug in the rat showed that most of the radioactivity was excreted in the feces and that significant quantities of 14C were sequestered by depot fat. Monkeys and human subjects both eliminated Win 35,833 primarily through the kidneys. The drug was excreted in rat bile and human urine, both as the free acid and conjugated with glucuronic acid. At physiological concentrations, Win 35,833 was extensively bound to rat, monkey, and human plasma proteins. A gas-chromatographic method for the analysis of drug in plasma, urine, or bile gave a linear relationship between peak height ratios and concentrations, in the range of 1-60 mug/ml.