CXY-001单次给药和反复给药的毒代动力学研究  

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

作　　者：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] 

机构地区：[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

出　　处：《癌变．畸变．突变》2009年第3期230-233,共4页Carcinogenesis,Teratogenesis & Mutagenesis

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、1 150 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。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 I, 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. C 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.

关 键 词：CXY-001 毒代动力学 药物暴露 

分 类 号：R969.1[医药卫生—药理学] R992[医药卫生—药学]