【作者】 许俊羽； 赵侠； 吴艳； 涂平； 孙培红； 周颖； 梁雁； 陈笑艳； 张逸凡； 陶纪宁； 崔一民；

【Author】 XU Jun-yu~1,ZHAO Xia~1,WU Yan~2,TU Ping~2,SUN Pei-hong~1,ZHOU Ying~1,LIANG Yan~1,CHEN Xiao-yan~3, ZHANG YI-fan~3,TAO Ji-ning~4,CUI Yi-min~1 (1.Department of Pharmacy,Peking University First Hospital,Beijing 100034,China; 2.Department of Dermatology,Peking University First Hospital,Beijing 100034,China; 3.Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China 4.Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co,Ltd,Shanghai 201210,China)

【机构】 北京大学 第一医院药剂科； 北京大学 第一医院皮肤性病科； 上海药物代谢研究中心； 上海复旦张江生物医药股份有限公司；

【摘要】 目的研究健康受试者单剂量静脉注射海姆泊芬后的药代动力学的性别差异、物料平衡及给药后光毒性反应。方法 16名健康受试者,男女各半,剂量5mg·kg^-1,分2批进行试验,每批8名,仅在第2批受试者中进行粪样采集,第2批受试者光毒试验的方法根据第1批受试者的光毒试验结果进行调整。采用经验证过的LC-MS/MS法测定血浆、尿液和粪便中海姆泊芬及其代谢产物血卟啉的含量。药代动力学参数采用WinNonlin计算。结果海姆泊芬原型药物（MHD）、代谢产物血卟啉（HP）主要药代动力学参数分别为C_max为（46.7±8.41）μg·ml^-1、（1.04±0.265）μg·ml^-1;T_max为0.333（0.333,0.417）h、0.333（0.333,0.500）h;t_1/2为（5.09±0.945）h、（5.71±2.65）h;AUC_0-24h为（29.8±6.19）h·μg·ml^-1、（0.757±0.285）h·μg·ml^-1;AUC_O-∞为（29.8±6.2）h·μg·ml^-1、（0.792±0.308）h·μg·ml^-1;给药后0-96 h,尿中MHD的累积排泄百分率仅占给药剂量的0.132%（n=15）,尿中HP的浓度很低,不足MHD的10%,未进行定量分析;粪便中MHD的累积排泄百分率为45.3%,HP为1.05%（n=8）。给药后52小时,日光模拟器、532nm治疗激光、室外日光三种光源照射都不引起光毒反应。结论单剂量静脉注射海姆泊芬后,MHD和HP的药动学参数在男女性别间未见统计学差异:原型药物和主要代谢产物主要经粪便排出;给药后52小时,三种光源照射都不引起光毒性反应。更多还原

【Abstract】 Objective To evaluate sex differences in pharmacokinetics and phototoxic reaction of hemoporfin after single intravenous in healthy subjects.Methods 16 healthy subjects,male and female,dosage 5mg·kg^-1. Two batches were tested,each batch of eight,fecal samples were collected only in the second batch subjects.How to develop phototoxicity test of the second batch of subjects was according to the first batch of subjects’ results. The concentrations of hemoporfin（MHD） and its major metabolites,haematoporphyrin（HP）,in plasma,urine and fecal were determined by LC-MS/MS.The pharmacokinetic parameters were calculated by WinNonlin program. Results The main pharmacokinetic parameters of hemoporfin and haematoporphyrin were as follows:C_max were （46.7±8.41） and（1.04±0.265）μg·ml^-1;T_max were 0.333（0.333,0.417） and 0.333（0.333,0.500） h;t_1/2 were （5.09±0.945） and（5.71±2.65） h;AUC_0-24hwere（29.8±6.19） and（0.757±0.285） h·μg·ml^-1;AUC_0-∞were（29.8±6.2） and（0.792±0.308） h·μg·ml^-1.96-hour cumulative urinary excretion rate of unchanged drug accounted for only 0.132%（n = 15）.Concentration of HP in urine was less than 10%,without a quantitative analysis.96-hour cumulative fecal excretions rate of MHD and HP were 45.3%and 1.05%（? = 8）.After administration 52 hours, exposure to the daylight simulator,532nm laser treatment and sunlight outdoor do not cause phototoxic reactions. Conclusion No significant differences were observed in pharmacokinetics parameters between male and female subjects after single intravenous hemoporfin;parent drug and major metabolites were excreted mainly in the faeces; After administration 52 hours,three kinds of light source do not cause phototoxic reactions.更多还原