克拉霉素缓释胶囊人体相对生物利用度研究

 目的建立人血浆中克拉霉素浓度测定的LC-MS/MS方法,研究克拉霉素缓释胶囊与市售克拉霉素缓释片的药动学及人体相对生物利用度。方法以罗红霉素为内标,用乙醚-二氯甲烷(3∶2)提取处理,以甲醇-水-甲酸(80∶20∶0.05)为流动相,用C18柱分离,采用ESI源,正离子方式检测,扫描方式为多反应监测(MRM)。结果克拉霉素线性范围为10.0～4000μg·L^-1,日内、日间RSD均小于15%。应用此方法研究18名健康受试者口服0.5g受试制剂和参比制剂的药动学参数。单剂量口服受试制剂和参比制剂的t_max,ρ_max,t_1/2,AUC_0-t,AUC_0-∞,CL和Vd分别为:(5.36±1.14)和(5.25±0.88)h,(1218±433)和(1333±370)μg·L^-1,(4.59±1.67)和(4.24±2.10)h,(8239±1553)和(8467±1364)μg·h·L^-1,(8662±1829)和(8795±1331)μg·h·L^-1,(60.9±15.1)和(58.9±11.3)L·h^-1和(382±103)和(366±224)L。多剂量口服受试制剂和参比制剂的t_max,ρ_ssmax,ρ_ssmin,ρ_av,AUC_ss和DF分别为:(5.31±1.11)和(5.28±0.96)h,(1387±396)和(1488±401)μg·L^-1,(64.6±26.8)和(70.1±30.0)μg·L^-1,(399±99.2)和(410±107)μg·L^-1,(9585±2382)和(9830±2578)μg·h·L^-1,(3.32±0.62)和(3.49±0.66)。单剂量和多剂量相对生物利用度分别为(98.2±16.3)%和(99.5±19.0)%。结论本法快速、准确、专属、灵敏。统计结果表明,两制剂人体内相对生物利用度无显著性差异(P>0.05)。

Studies of Relative Bioavailability of Clarithromycin Sustained-Release Capsules

OBJECTIVE To establish a LC-MS/MS method for the determination of clarithromycin in human plasma and to study pharmacokinetics and relative bioavailability of clarithromycin sustained-release capsule and clarithromycin sustained-release tablet in market. METHODS The tested drug and internal standard roxithromycin were extracted from plasma samples by ether-dichloromethane(3∶2) and chromatgraphed on a C₁₈ column. The mobile phase consisted of methanol-water-formic acid (80∶20∶0.05).Detection was performed on a triple quadrupole tandem mass spectrometer via electrospray ionization source(ESI) in the positive mode. RESULTS The linear calibration curves were obtained in the concentration range of 10.0～4 000 μg·L^-1. The intra-and inter-run precisions were lower than 15% in terms of relative standard deviation. Pharmacokinetic parameters of the two products after the administration of 0.5 g clarithromycin to 18 volunteers were as follows:t_max(5.36±1.14) and (5.25±0.88) h,ρ_max(1 218±433) and (1 333±370)μg·L^-1,t_1/2(4.59±1.67) and (4.24±2.10)h,AUC_0-t(8 239±1 553) and (8 467±1 364)μg·h·L^-1,AUC_0-∞(8 662±1 829) and (8 795±1 331)μg·h·L^-1,CL(60.9±15.1) and (58.9±11.3)L·h^-1,Vd(382±103) and (366±224)L,for a single dose,respectively;t_max(5.31±1.11) and (5.28±0.96) h,ρ_ssmax (1 387±396) and (1 488±401) μg·L^-1,ρ_ssmin(64.6±26.8) and (70.1±30.0) μg·L^-1,ρ_av(399 ±99.2) and (410±107) μg·L^-1,AUC_ss(9 585±2 382) and (9 830±2 578) μg·h·L^-1,DF(3.32±0.62) and (3.49±0.66) for multiple doses,respectively. The relative bioavailability of the test drug for single dose and multiple doses were(98.2±16.3)% and (99.5±19.0)%. CONCLUSION This method is fast,sensitive and accurary.There is no difference between the test and the reference drugs of clarithromycin in the relative bioavailability (P>0.05).