Frantz S W, Beskitt J L, Grosse C M, Tallant M J, Dietz F K, Ballantyne B
Bushy Run Research Center.
Drug Metab Dispos. 1996 Aug;24(8):911-21.
The pharmacokinetics of [1,2-14C]ethylene glycol (EG) were evaluated in female Sprague-Dawley rats and CD-1 mice to characterize the plasma disposition after intravenous (IV), peroral (PO), and percutaneous (PC) doses. Rats were given doses of 10 or 1000 mg/kg by each route, and additional PO doses of 400, 600, or 800 mg/kg. Mice were also given IV and PO (bolus gavage) doses of 10 or 1000 mg/kg, and additional PO doses of 100, 200, or 400 mg/kg. PC doses in mice were 100 or 1000 mg/kg, and both species were given a 1000 mg/kg PC dose with a 50% (w/w) aqueous solution (2 ml/kg) to simulate antifreeze exposure. Results from this study have shown that orally-administered EG is very rapidly and almost completely absorbed in both rats and mice, with a bioavailable fraction of 92-100% in rats and similar percentages at the higher doses in mice. In contrast, the absorption of cutaneously applied EG is comparatively slow in both species. A species difference in the overall absorption of PC doses was demonstrated, with higher recoveries of 14C observed after PC doses in mice than for rats and a greater penetration of 14C after applying a 50% aqueous PC dose in mice than in rats, as evidenced by quantifiable plasma 14C concentrations only in mice. The major metabolites in both rats and mice are CO2 and glycolate. Oxidative metabolic pathways are saturated at high PO doses in both species, resulting in a shift from exhaled CO2 as the major excretion route to urinary excretion. The capacity to metabolize more completely EG to CO2 at low doses seems to be greater in the mouse than in the rat, as evidenced by the absence of urinary oxalate from EG-dosed female mice, and saturation of metabolic pathways at a comparatively lower dose in mice than for rats. This evidence suggests that dose-dependent changes in EG excretion in female Sprague-Dawley rats and CD-1 mice probably resulted from capacity-limited effects on EG metabolic pathways for the production of CO2 and a compensatory urine clearance of glycolate. Results from the present study corroborate previous observations in rats for the lower doses, but demonstrate a substantial difference in single-dose pharmacokinetics for IV and PO 1000 mg/kg doses in mice vs. rats. In summary, these data indicate that mice show a nonlinear plasma disposition of total radioactivity (EG and its metabolites) as dose is increased, whereas in rats plasma kinetics were linear over the dose range evaluated, whereas excretion kinetic patterns were nonlinear in both species as dose is increased.
对雌性斯普拉格-道利大鼠和CD-1小鼠进行了[1,2-¹⁴C]乙二醇（EG）的药代动力学评估，以表征静脉注射（IV）、口服（PO）和经皮（PC）给药后的血浆处置情况。通过每种给药途径给大鼠分别给予10或1000 mg/kg的剂量，以及额外400、600或800 mg/kg的口服剂量。也给小鼠静脉注射和口服（大剂量灌胃）10或1000 mg/kg的剂量，以及额外100、200或400 mg/kg的口服剂量。小鼠的经皮给药剂量为100或1000 mg/kg，两种动物均给予1000 mg/kg的经皮给药剂量，用50%（w/w）的水溶液（2 ml/kg）以模拟接触防冻液的情况。该研究结果表明，口服给予的EG在大鼠和小鼠中均能非常迅速且几乎完全被吸收，大鼠的生物利用度分数为92%-100%，小鼠在较高剂量时的百分比相似。相比之下，两种动物经皮应用的EG吸收相对较慢。经皮给药剂量的总体吸收存在种属差异，小鼠经皮给药后¹⁴C的回收率高于大鼠，且小鼠应用50%经皮水溶液剂量后¹⁴C的渗透程度大于大鼠，仅在小鼠中可检测到血浆¹⁴C浓度即可证明。大鼠和小鼠的主要代谢产物均为二氧化碳和乙醇酸。两种动物在高口服剂量时氧化代谢途径均饱和，导致主要排泄途径从呼出二氧化碳转变为经尿液排泄。在低剂量下将EG更完全地代谢为二氧化碳的能力在小鼠中似乎比在大鼠中更强，这可通过给EG的雌性小鼠尿液中无草酸盐以及小鼠代谢途径在相对较低剂量时饱和而大鼠未饱和得到证明。这一证据表明，雌性斯普拉格-道利大鼠和CD-1小鼠中EG排泄的剂量依赖性变化可能是由于对EG代谢途径产生二氧化碳的能力限制效应以及乙醇酸的代偿性尿液清除所致。本研究结果证实了先前在大鼠中对较低剂量的观察结果，但表明小鼠与大鼠相比，静脉注射和口服1000 mg/kg剂量的单剂量药代动力学存在显著差异。总之，这些数据表明，随着剂量增加，小鼠中总放射性（EG及其代谢产物）的血浆处置呈非线性，而在大鼠中，在所评估的剂量范围内血浆动力学呈线性，而随着剂量增加，两种动物的排泄动力学模式均呈非线性。
