Comparative metabolism and kinetics of coumarin in mice and rats
Comparative metabolism and kinetics of coumarin in mice and rats
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DOI：
10.1016/s0278-6915(02)00227-2
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发表时间：
2003-02-01
影响因子：
4.3
通讯作者：
Hawkins, DR
中科院分区：
文献类型：
--
作者：
Born, SL;Api, AM;Hawkins, DR
香豆素是一种公认的大鼠肝毒物，也可引起小鼠肺末细支气管Clara细胞急性选择性坏死。此外，慢性灌胃香豆素200mg /kg（该剂量可导致Clara细胞死亡）导致B6C3F1小鼠肺泡/细支气管腺瘤和癌的发生率显著增加。相比之下，在口服灌胃研究中，在100和50 mg/kg剂量水平下，或在CD-1小鼠长期摄入相当于276 mg/kg剂量的香豆素后，未观察到小鼠肺部肿瘤。本研究旨在确定口服灌胃与膳食给药对CD-1和6BC3F1小鼠以及F344大鼠香豆素的药代动力学和代谢的影响。通过灌胃给药200 mg/kg c -14-香豆素后，肺C-max值（总c -14相关放射性）分别比口服50 mg/kg剂量或饲料中1000 ppm的剂量高5倍和37倍。香豆素（200 mg/kg）灌胃后在F344大鼠体内进行药代动力学和代谢测定。血浆中与c -14-角马素相关的总放射性比小鼠低3.5倍，血浆半衰期比小鼠长5倍。采用非放射性标记化合物（200 mg/kg），对小鼠和大鼠灌胃后血浆和尿液中的香豆素及香豆素3,4-环氧化途径产物进行定量分析。测定小鼠血浆和尿液中7-羟基香豆素（7-HC）含量。o-羟基苯基乙酸（o-HPAA）在血浆中的浓度达到37马克杯/毫升，占尿中剂量的41%，而7-羟基香豆素的C-max为3马克杯/毫升，占给药剂量的7%。大鼠血浆中o-HPAA的C-max为6杯/毫升，占给药剂量的12%。大鼠血浆中香豆素C-max含量与小鼠相当。香豆素3,4-环氧化物（CE）及其重排产物o-羟基苯基乙醛（o-HPA）和o-羟基苯基乙醇（o-HPE）在血浆或尿液中的任何时间点均未检测到。香豆素和CE在啮齿类动物体内的药代动力学分析表明，小鼠口服灌胃和饮食生物测定中不同的肿瘤反应是暴露途径的一个功能，而小鼠和大鼠之间肺毒性的物种差异是小鼠肺部局部生物活性增强的结果。2003爱思唯尔科学有限公司版权所有。
Coumarin, a well recognized rat hepatotoxicant, also causes acute, selective necrosis of terminal bronchiolar Clara cells in the mouse lung. Further, chronic oral gavage administration of coumarin at 200 mg/kg, a dose that causes Clara cell death, resulted in a statistically significant increased incidence of alveolar/bronchiolar adenomas and carcinomas in B6C3F1 mice. In contrast, mouse lung tumors were not observed at the 100 and 50 mg/kg dose levels in the oral gavage study, or in CD-1 mice following chronic intake of coumarin at levels equivalent to 276 mg/kg in diet. The current studies were designed to determine the impact of oral gavage vs dietary administration on the pharmacokinetics and metabolism of coumarin in CD-1 and 6BC3F1 mice and F344 rats. Following the administration of 200 mg/kg C-14-coumarin via oral gavage, lung C-max values (total C-14-associated radioactivity) were five- and 37-fold greater than those resulting from a 50 mg/kg oral gavage dose or 1000 ppm in diet, respectively. Coumarin (200 mg/kg) pharmacokinetics and metabolism was also examined in F344 rats following oral gavage dosing. Total C-14-cournarin associated radioactivity in plasma was 3.5-fold lower than in the mouse, and the plasma half-life in rats was five-times longer than in mice. Using non-radiolabeled compound (200 mg/kg), coumarin and products of the coumarin 3,4-epoxidation pathway were quantitated in plasma and urine after oral gavage administration to mice and rats. 7-Hydroxycoumarin (7-HC) was quantitated in mouse plasma and urine. o-Hydroxyphenylacetic acid (o-HPAA) reached a concentration of 37 mug/ml in plasma, and accounted for 41% of the dose in the urine, whereas the C-max for 7-hydroxycoumarin was 3 mug/ml, and represented 7% of the administered dose. In the rat, the plasma C-max for o-HPAA was 6 mug/ml, and accounted for 12% of the dose. The coumarin C-max in rat plasma was comparable to that in mouse. Coumarin 3,4-epoxide (CE) and its rearrangement product o-hydroxyphenylacetaldehyde (o-HPA) and o-hydroxyphenylethanol (o-HPE), were not detected at any time point in plasma or urine. This analysis of coumarin and CE pharmacokinetics in rodents suggests that the differential tumor response in the mouse oral gavage and dietary bioassays is a function of the route of exposure, whereas species differences in lung toxicity between mice and rats result from heightened local bioactivation in the mouse lung. (C) 2003 Elsevier Science Ltd. All rights reserved.