摘要
目的 研究小分子抑制剂SYHA1809在比格犬体内的药动学。方法 采用液相色谱-串联质谱(LC-MS/MS)法进行测定。将比格犬随机分为单次静脉给药组(3.75 mg/kg)、单次低剂量灌胃组(3.75 mg/kg)、单次中剂量灌胃组(7.5 mg/kg)、单次高剂量灌胃组(15 mg/kg)和多次灌胃组(7.5 mg/kg,每天1次,连续7 d),每组6只,雌雄各半。各组比格犬按照设定的时间点收集血浆样品,经预处理后进行LC-MS/MS定量分析,获得的数据采用Phoenix WinNonlin 8.0软件计算药动学参数。结果 SYHA1809静脉注射给药后,在比格犬体内的CL为(2.70±0.48) mL/(min·kg),稳态分布体积为0.757 L/kg,t_(1/2)为(3.35±1.36) h;单次灌胃给予低、中、高剂量的SYHA1809后,其在比格犬体内的平均t_(max)为(0.53±0.02) h,血药浓度随给药剂量的增加而升高;单次灌胃给予3.75mg/kg的SYHA1809后,绝对生物利用度为83.5%;在3.75~15 mg/kg剂量范围内,SYHA1809的c_(max)和AUC增加与剂量呈正相关;SYHA1809连续以7.5 mg/kg灌胃7 d后,与同剂量单次灌胃给药后的药动学参数相当,差异无统计学意义(P>0.05)。结论SYHA1809在比格犬体内吸收迅速,血药浓度呈剂量依赖性,生物利用度高,多次灌胃给药后无明显蓄积,药动学行为良好。
OBJECTIVE To study the pharmacokinetics of small molecule inhibitor SYHA1809 in Beagle dogs.METHODS LC-MS/MS method was adopted.Beagle dogs were randomly divided into single intravenous administration group(3.75 mg/kg),single low-dose intragastric administration group(3.75 mg/kg),single medium-dose intragastric administration group(7.5 mg/kg),single high-dose intragastric administration group(15 mg/kg) and multiple intragastric administration group(7.5 mg/kg,once a day,for 7 consecutive days),with 6 dogs in each group,half male and half female.The plasma samples of Beagle dogs were collected in each group according to the set time point,and underwent LC-MS/MS quantitative analysis after preprocessing.The pharmacokinetic parameters were calculated by using Phoenix WinNonlin 8.0 software using obtained data.RESULTS After intravenous injection,CL of SYHA1809 in Beagle dogs was(2.70±0.48) mL/(min·kg),steady-state distribution volume was 0.757 L/kg,and t_(1/2) was(3.35±1.36) h;after single intragastric administration of low-dose,medium-dose and high-dose of SYHA1809,average t_(max) was(0.53±0.02) h,and the blood drug concentration increased with the increase of dose;after single intragastric administration of 3.75 mg/kg SYHA1809,the absolute bioavailability was 83.5%;within the dose range of 3.75-15mg/kg,the increase in c_(max) and AUC of SYHA1809 was positively correlated with the dose;after intragastric administration of 7.5mg/kg SYHA1809 for 7 consecutive days,the pharmacokinetic parameters of SYHA1809 were comparable to those of a single intragastric administration of the same dose,with no statistically significant difference(P>0.05).CONCLUSIONS SYHA1809 is absorbed rapidly in Beagle dogs,shows the dose-dependent blood concentration,high bioavailability,no obvious accumulation after multiple intragastric administration,and good pharmacokinetic behavior.
作者
刘晓琳
杨汉煜
王小彦
康凯
梁敏
LIU Xiaolin;YANG Hanyu;WANG Xiaoyan;KANG Kai;LIANG Min(College of Pharmacy,Hebei Medical University,Shijiazhuang 050011,China;CSPC Zhongqi Pharmaceutical(Shijiazhuang)Co.,Ltd.,Shijiazhuang 050035,China)
出处
《中国药房》
CAS
北大核心
2023年第17期2085-2089,共5页
China Pharmacy
基金
河北省科技研发平台建设专项(No.199676133H)。
作者简介
第一作者:刘晓琳,硕士。研究方向:体内药物代谢动力学。E-mail:liuxiaolin6101998@163.com;通信作者:杨汉煜,正高级工程师,硕士。研究方向:体内药物代谢动力学。E-mail:yanghanyu@cspc.cn。
