阿德福韦酯类似物M_1和M_2在犬体内的生物利用度研究

Bioavailability Study of Adefovir Dipivoxil Analogs M_1 and M_2 in Dogs

目的:研究阿德福韦酯类似物M1和M2在犬体内的生物利用度。方法:将犬随机分为阿德福韦酯组、M1组和M2组,每组6只,灌服相应药物7mg/kg,采用高效液相色谱-质谱法检测各组犬给药后0.33、0.67、1、2、3、4、8、12、24、36、48h阿德福韦的血药浓度,用3p97药动学软件计算药动学参数。色谱柱:Phenomenex C18(2)100d,预柱:Luna C18(2),流动相:1%甲酸水溶液-甲醇(98:2,V/V),流速:0.2ml/min;质谱条件:电喷雾电离选择性正离子检测,阿德福韦测定离子质荷比(m/z)为274[M+H]+,内标更昔洛韦测定离子m/z为256[M+H]+。结果:阿德福韦酯、M1和M2的药动学参数分别为tmax:(0.69±0.14)、(1.30±0.98)、(1.23±1.00)h,cmax:(143.19±56.79)、(48.11±18.45)、(79.76±41.68)ng/ml,AUC0-48h:(2559.80±896.64)、(966.91±668.36)、(954.16±1405.65)ng·h/ml,M1和M2的生物利用度分别为37.77%和37.27%。结论:M1和M2的生物利用度未达临床需求,其原因可能是合成或纯化过程中杂质过多,或者其体内转化有限,尚待进一步探究。

OBJECTIVE：To investigate the bioavailability of adefovir dipivoxil analogs M1 and M2 in dogs.METHODS：Dogs were randomly divided into adefovir dipivoxil group,M1 group and M2 group with 6 dogs for each group.These groups were given appropriate drugs of 7 mg/kg.The plasma concentrations of adefovir were measured by HPLC-MS 0.33,0.67,1,2,3,4,8,12,24,36,48 h after administration.The pharmacokinetic parameters were measured by 3p97 software.The chromatographic condition was as follows：Phenomenex C18（2）100 d column,Luna C18（2）pre-column,1% formic acid-methanol（98：2,V/V）,flow rate of 0.2 ml/min;MS condition：electrospray ionization selective positive ion detection,（m/z）274[M＋H]＋ for adefovir and m/z 256[M＋H]＋ for ganciclovir.RESULTS：Pharmacokinetic parameters of adefovir dipivoxil,M1 and M2 were as follows：tmax：（0.69±0.14）,（1.30±0.98）,（1.23±1.00）h;cmax：（143.19±56.79）,（48.11±18.45）,（79.76±41.68）ng/ml;AUC0-48 h：（2 559.80±896.64）,（966.91±668.36）,（954.16±1 405.65）ng·h/ml.The relative bioavailability of M1 and M2 were 37.77% and 37.27%,respectively.CONCLUSIONS：The bioavailability of M1 and M2 have not achieved clinical requirement.The cause that there was large number of impurity during synthetise or purification and transformation is limited in vivo,should be further studied.