Abbas R, Fisher J W
Toxicology Division, Geo-Centers, Inc., Wright-Patterson Air Force Base, Ohio 45433-7400, USA.
Toxicol Appl Pharmacol. 1997 Nov;147(1):15-30. doi: 10.1006/taap.1997.8190.
A six-compartment physiologically based pharmacokinetic (PBPK) model for the B6C3F1 mouse was developed for trichloroethylene (TCE) and was linked with five metabolite submodels consisting of four compartments each. The PBPK model for TCE and the metabolite submodels described oral uptake and metabolism of TCE to chloral hydrate (CH). CH was further metabolized to trichloroethanol (TCOH) and trichloroacetic acid (TCA). TCA was excreted in urine and, to a lesser degree, metabolized to dichloroacetic acid (DCA). DCA was further metabolized. The majority of TCOH was glucuronidated (TCOG) and excreted in the urine and feces. TCOH was also excreted in urine or converted back to CH. Partition coefficient (PC) values for TCE were determined by vial equilibrium, and PC values for nonvolatile metabolites were determined by centrifugation. The largest PC values for TCE were the fat/blood (36.4) and the blood/air (15.9) values. Tissue/blood PC values for the water-soluble metabolites were low, with all PC values under 2.0. Mice were given bolus oral doses of 300, 600, 1200, and 2000 mg/kg TCE dissolved in corn oil. At various time points, mice were sacrificed, and blood, liver, lung, fat, and urine were collected and assayed for TCE and metabolites. The 1200 mg/kg dose group was used to calibrate the PBPK model for TCE and its metabolites. Urinary excretion rate constant values were 0. 06/hr/kg for CH, 1.14/hr/kg for TCOH, 32.8/hr/kg for TCOG, and 1. 55/hr/kg for TCA. A fecal excretion rate constant value for TCOG was 4.61/hr/kg. For oral bolus dosing of TCE with 300, 600, and 2000 mg/kg, model predictions of TCE and several metabolites were in general agreement with observations. This PBPK model for TCE and metabolites is the most comprehensive PBPK model constructed for P450-mediated metabolism of TCE in the B6C3F1 mouse.
针对三氯乙烯（TCE）构建了一个用于B6C3F1小鼠的六室生理药代动力学（PBPK）模型，并将其与五个代谢物子模型相连接，每个代谢物子模型由四个室组成。TCE的PBPK模型以及代谢物子模型描述了TCE经口服吸收并代谢为水合氯醛（CH）的过程。CH进一步代谢为三氯乙醇（TCOH）和三氯乙酸（TCA）。TCA经尿液排泄，且在较小程度上代谢为二氯乙酸（DCA）。DCA进一步代谢。大多数TCOH经葡萄糖醛酸化（TCOG）后经尿液和粪便排泄。TCOH也经尿液排泄或转化回CH。TCE的分配系数（PC）值通过小瓶平衡法测定，非挥发性代谢物的PC值通过离心法测定。TCE的最大PC值为脂肪/血液（36.4）和血液/空气（15.9）的值。水溶性代谢物的组织/血液PC值较低，所有PC值均低于2.0。给小鼠经口灌胃给予溶解于玉米油中的300、600、1200和2000mg/kg的TCE。在不同时间点处死小鼠，并收集血液、肝脏、肺、脂肪和尿液，检测其中的TCE和代谢物。1200mg/kg剂量组用于校准TCE及其代谢物的PBPK模型。CH的尿排泄速率常数为0.06/小时/千克，TCOH为1.14/小时/千克，TCOG为32.8/小时/千克，TCA为1.55/小时/千克。TCOG经粪便排泄的速率常数为4.61/小时/千克。对于300、600和2000mg/kg的TCE经口灌胃给药，TCE和几种代谢物的模型预测结果与观察结果总体一致。这个TCE及其代谢物的PBPK模型是针对B6C3F1小鼠中P450介导的TCE代谢构建的最全面PBPK模型。
