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.

Animals↗

PubMedDate not supplied

Metabolism and disposition of sulfinalol in laboratory animals.

Peak levels of radioactivity in blood occurred 1.0 hr after oral administration of 3H-sulfinalol hydrochloride to rats, dogs, and monkeys. The plasma decay curve for intact sulfinalol in the dog was biphasic, with apparent first-order half-lives of 0.55 and 6.2 hr. Rats excreted 42.5% of the dose in the urine and 31.8% in the feces after 24 hr. Urinary and fecal recovery were 53.8% and 41.2%, respectively, after 10 days for dogs and 57.8% and 38.0%, respectively, after 9 days for monkeys. Free sulfinalol (11.8% of the dose) was the major component in dog feces with lesser amounts of the sulfide and sulfone metabolites, also in the unconjugated form. All metabolites in dog urine were conjugated with glucuronic acid, with sulfinalol (28.5%) and desmethylsulfinalol (8.5%) representing the major constituents, whereas the sulfone and sulfide metabolites were minor ones. Monkey feces contained primarily unconjugated forms of the desmethyl sulfide metabolite (17.0%) and sulfinalol (7.5%); lesser amounts of desmethylsulfinalol and the sulfone metabolite were present. Desmethylsulfinalol (8.7%) and its sulfate (7.0%) and glucuronide (4.0%) conjugates were the major urinary metabolites in the monkey; sulfinalol (1.4%), its glucuronide conjugate (5.1%), the desmethyl sulfide metabolite (and its sulfate conjugate), and the sulfone metabolite were also present.

Animals↗