Casterton Phillip L, Crincoli Christine M, Brathwaite Witty A, Rihner Marisa O, Nikiforov Andrey I, Thomas Jennifer A
Cargill, Inc, Scientific & Regulatory Affairs, Wayzata, MN, USA.
Cargill, Inc, Scientific & Regulatory Affairs, Wayzata, MN, USA
Int J Toxicol. 2014 May;33(3):238-245. doi: 10.1177/1091581814528362. Epub 2014 Apr 3.
[C]-Labeled arruva [sodium/potassium (2R,4R)-2-amino-4-carboxy-4-hydroxy-5-(3-indolyl) pentanoate] was administered as a single gavage dose (10 mg/kg bw) to male and female Beagle dogs and 1 bile duct-cannulated male. The mean peak arruva plasma concentration equivalent of 1.2 µg/g occurred at first sampling time point of 1 hour postdosing. The mean area under the concentration versus time curve from 0 hour postdosing to the last time point was approximately 20 µg·h/g and the mean terminal plasma elimination half-life ranged from 15 hours in females to 21 hours in males. Over 168 hours postdosing, 35% to 50% of the administered arruva was eliminated in the urine with 44% to 53% eliminated in feces; 1.3% of the administered dose was recovered in bile. Arruva and its derivatives were identified using tandem mass spectrometry, and the relative percentage of each substance was quantified via radio high-performance liquid chromatography. Over a 168-hour collection period, combined urine and feces extract data from the 6 noncannulated dogs showed that approximately 91% of the dose was excreted as unchanged parent arruva (41% in urine and 50% in feces). In the cannulated male, 95.3% was excreted as unchanged parent arruva; 50.2% in urine, 43.9% in feces, and 1.3% in bile. Lactone and lactam derivatives of arruva and 1 unidentified substance were detected in urine only during the first 24 hours postdosing with the greatest amounts detected during the first 6 hours of collection; up to 1% of lactone or lactam derivatives were detected in bile samples. Plasma pharmacokinetics data indicated rapid absorption of arruva with the majority of radioactivity located in the feces collected in the first 48 hours.
给雄性和雌性比格犬以及1只胆管插管的雄性犬经口灌胃给予单剂量[C]标记的阿鲁瓦（[钠/钾 (2R,4R)-2-氨基-4-羧基-4-羟基-5-(3-吲哚基)戊酸酯]）（10 mg/kg体重）。给药后1小时的首个采样时间点，阿鲁瓦的平均血浆峰浓度相当于1.2 µg/g。给药后0小时至最后一个时间点的浓度-时间曲线下面积平均值约为20 µg·h/g，血浆消除终末半衰期平均值在雌性中为15小时，在雄性中为21小时。给药后168小时内，给药的阿鲁瓦有35%至50%经尿液排出，44%至53%经粪便排出；给药剂量的1.3%在胆汁中回收。使用串联质谱法鉴定阿鲁瓦及其衍生物，并通过放射性高效液相色谱法对每种物质的相对百分比进行定量。在168小时的收集期内，6只未插管犬的尿液和粪便提取物合并数据显示，约91%的剂量以未变化的母体阿鲁瓦形式排出（41%经尿液排出，50%经粪便排出）。在插管的雄性犬中，95.3%以未变化的母体阿鲁瓦形式排出；50.2%经尿液排出，43.9%经粪便排出，1.3%经胆汁排出。仅在给药后的前24小时内在尿液中检测到阿鲁瓦的内酯和内酰胺衍生物以及1种未鉴定物质，在收集的前6小时内检测到的量最大；胆汁样本中检测到高达1%的内酯或内酰胺衍生物。血浆药代动力学数据表明阿鲁瓦吸收迅速，大部分放射性位于给药后前48小时收集的粪便中。
