Geary R S, Swynnerton N F, Miller M A, Mangold D J, Ludden T
Southwest Research Institute, San Antonio, Texas 78284.
Res Commun Chem Pathol Pharmacol. 1989 Aug;65(2):147-59.
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.
在三只健康雄性恒河猴身上进行了乙硫磷（WR - 2721）的剂量递增交叉研究。每只受试动物接受了三种十二指肠内单次给药，剂量分别为150、300和600mg/kg。根据时间采集血样，采用高效液相色谱电化学检测法测定乙硫磷、WR - 1065（游离硫醇代谢物）以及可转化为游离硫醇的总药物（总WR - 1065）的浓度。在所有三个剂量水平下，血浆中乙硫磷水平通常低于可检测定量限（0.23μmol/L），但游离WR - 1065血浆水平随剂量增加而升高。对游离WR - 1065生物利用度值的分析表明，受试动物之间存在很大变异性且剂量反应不可预测。结合型WR - 1065在整个剂量范围内似乎达到饱和水平，这表明血浆中存在一个可饱和的结合位点池。无论给药剂量如何，WR - 1065的血浆峰值时间都是可变的，范围为1.0 - 2.5小时。数据中的高变异性可能是由于母体化合物（乙硫磷）的渗透性或吸收性差、与血浆中可变结合位点池的可饱和结合和/或乙硫磷在肠道腔、肠壁（上皮）和肝脏中的高首过代谢所致。
