Intraduodenal administration of ethiofos (WR-2721): dose proportionality study in the rhesus monkey.
A dose progression crossover study of ethiofos (WR-2721) was conducted in three healthy male rhesus monkeys. Each subject was tested with three single intraduodenal doses containing 150, 300, and 600 mg/kg. Blood samples were drawn as a function of time and the concentrations of ethiofos, WR-1065 (free thiol metabolite), and total drug convertible to the free thiol (total WR-1065) were determined by HPLC using electrochemical detection. Ethiofos levels in plasma were usually below quantifiable limits of detection (0.23 mumol/L) at all three dose levels, but free WR-1065 plasma levels increased with increasing dose. Analysis of the free WR-1065 bioavailability values indicated large variability and an unpredictable dose response among subjects. Bound WR-1065 appears to reach saturable levels over the dose range, suggesting a saturable pool of binding sites in plasma. The time-to-peak plasma levels for WR-1065 were variable regardless of the administered dose and ranged from 1.0-2.5 hours. The high variability in the data may be a result of poor permeability or absorption of the parent compound (ethiofos), saturable binding to a variable pool of binding sites in plasma and/or high first-pass metabolism of ethiofos involving the gut lumen, gut wall (epithelium), and liver.
Geary
R S
RS
Southwest Research Institute, San Antonio, Texas 78284.
Swynnerton
N F
NF
Miller
M A
MA
Mangold
D J
DJ
Ludden
T
T
D004999:Amifostine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004386:Duodenum; D006801:Humans; D007441:Intubation, Gastrointestinal; D008253:Macaca mulatta; D008624:Mercaptoethylamines / Q000493:pharmacokinetics; D009946:Organothiophosphorus Compounds / Q000008:administration & dosage*
D008624:Mercaptoethylamines; D009946:Organothiophosphorus Compounds; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D004999:Amifostine