Intraduodenal administration of ethiofos (WR-2721) : dose proportionality study in the rhesus monkey
Geary, R.S.; Swynnerton, N.F.; Miller, M.A.; Mangold, D.J.; Ludden, T.
Research Communications in Chemical Pathology and Pharmacology 65(2): 147-159
1989
ISSN/ISBN: 0034-5164 PMID: 2555852 Document Number: 343754
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.