癌变·畸变·突变 ›› 2009, Vol. 21 ›› Issue (3): 230-233.doi: 10.3969/j.issn.1004-616x.2009.03.018

• 论著 • 上一篇    下一篇

CXY-001单次给药和反复给药的毒代动力学研究

靳洪涛1, 王国成2, 李万芳1, 李　慧1, 李　晋1, 王永锋2, 顾景凯3, 王爱平1   

  1. 1中国医学科学院药物研究所新药安评中心，北京　100050; 2天津天士力集团有限公司，天津　300402; 3 吉林大学药物代谢研究中心，长春　130021
  • 收稿日期:2009-01-09 修回日期:2009-02-24 出版日期:2009-05-30 发布日期:2009-05-30

Toxicokinetics of CXY-001 Following Single and Repeated Administration to Beagle Dogs

JIN Hong-tao1，WANG Guo-cheng2, LI Wan-fang1，LI Hui1, LI Jin1, WANG Yong-feng2，GU Jing-kai3，WANG Ai-ping1   

  1. 1. Centre of Drug Safety Evaluation，Institute of Materia Medica，Chinese Academy of Medical Sciences，Beijing 100050；2. Tianjin Tasly Group, Tianjin 300402; 3. Center of Drug Metabolism, Jilin Univerity, Changchun 130021,China
  • Received:2009-01-09 Revised:2009-02-24 Online:2009-05-30 Published:2009-05-30

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摘要： 背景与目的： 通过CXY-001药物在犬体内的毒代动力学的研究，探讨单次给药及反复给药的药物毒性反应与药物暴露量的相关性。 材料与方法： 分别对Beagle犬经口单次给予不同剂量的CXY-001药物，及反复给予不同剂量的CXY-001药物后，采用液相色谱-质谱-质谱(EC-MS-MS)方法检测犬血清中药物浓度，及观察犬的毒性反应。单次给药试验：给药剂量为227、511、767、1150 mg/kg，每个剂量用1只Beagle犬试验，分别于给药后0.5、1、2、3、4、5、6、8、24 h采血。反复给药试验：给药剂量分别为120、30、 7 mg/kg，连续给药90 d，停药后恢复期观察4周。首次给药后分别于0.5、1、2、3、4、5、6、8、24 h采血；给药中期(第45 d)采血点为药后0.5、5、24 h；末次给药(第90 d)后采血点分别为药后0.5、5、24、48、72和96 h，每组采血动物数为3只。 结果： 单次给药后Beagle犬主要反应为呕吐，227、511、767、1 150 mg/kg 4个剂量组单次给药AUC0-24依次为150 249、263 905、232 640和19 848 ng•h/ml；犬血清中AUCO-∞分别为151 054、 298 069、246 083和117 793 ng•h/ml；Cmax分别为13 400、19 500、29 100和6 910 ng/ml。反复给药120、30、7 mg/kg 3个剂量组首次给药后AUC0-24分别为(123 023±75 308)、(19 246±14 654)和(2 991±996) ng•h/ml，AUC0-∞分别为(200 189±106 688)、(25 145±22 443)和(4 650±1 855) ng•h/ml，Cmax分别为(10 440±5 891)、(3 653±1 776)和 (376±116) ng/ml，第45 d、第90 d相同时间点各组的血药浓度值有一定的波动，药后48 h动物体内血药浓度已低于检测线。仅30 mg/kg剂量组未见毒性作用。 结论： Beagle犬经口给予CXY-001后，在一定剂量范围内(约<600 mg)犬血清中Cmax、AUC0-24和AUC0-∞随着剂量的增加而增加；反复给药于停药后药物清除较快，提示该药连续给药后可能无蓄积作用。

关键词: CXY-001, 毒代动力学, 药物暴露

Abstract: BACKGROUND AND AIM: To study toxicokinetics of CXY-001 in Beagle dogs, and evaluate the relationship between exposure response and dose. MATERIALS AND METHODS: Samples were analyzed with a validated LC-MS-MS method. In single dose study, the dosages of CXY-001 were 227, 511, 767, 1150 mg/kg . Blood samples were collected at 0.5, 1,2,3,4,5,6,8, 24 h after administration. In the 90-day repeated dose study, CXY-001 dosages were 120,30 and 7 mg/kg . On day 1, blood samples were collected at 0.5, 1,2,3,4,5,6,8, 24 h after administration. On day 45, blood samples were collected at 0.5,5,24 h and on day 90 at 30 min, 5,24,48,72 h. RESULTS: In single dose study, vomiting was observed. The CXY-001 AUC0-24 for doses 227,511,767,1 150 mg/kg were 150 249,263 905,232 640 and 19 848 ng•h/ml,respectively. The AUC0-∞ were 151 054, 298 069, 246 083 and 117 793 ng•h/ml,respectively. The Cmax were 13 400, 19 500, 29 100 and 6 910 ng•h/ml, respectively. In repeated dose study, the No-Observed-Adverse-Effect-Levle was 30 mg/kg. On day 1, the CXY-001 AUC0-24 for doses 120,30 and 7 mg/kg were (123 023±75 308),(19 246±14 654) and (2 991±996) ng•h/ml,respectively. AUC0-∞ were (200 189±106 688),(25 145±22 443) and (4 650±1 855) ng•h/ml,respectively. Cmax were (10 440± 5 891), (3 653±1 776) and (376±116) ng•h/ml, respectively. There was a slight difference of CXY-001 concentration at the same time point on day 45 and day 90,and CXY-001 concentration was below the low limit of quantitation at 48 h after last dose. CONCLUSION: Exposure response to CXY-001 generally increased with increasing dosage in Beagle dogs following oral dosing. These data suggest no accumulation was observed after stopping CXY-001 administration.

Key words: CXY-001, toxicokinetics, drug exposure

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