9-硝基喜树碱犬体内药代动力学研究

Pharmacokinetics of 9-nitro-camptothecin in Beagle dogs

目的:研究9硝基喜树碱在犬体内药动学规律。方法:犬静注或灌服3个剂量9硝基喜树碱,血浆9硝基喜树碱浓度用高效液相色谱法及液相质谱联用法检测,浓度时间数据用3P97药代动力学软件进行分析,计算药动学参数,分析AUC、Cmax及ke与剂量的线性关系。结果:犬静注0.5、1、2mg·kg-19硝基喜树碱,t12分别为2.2±2.2、1.8±1.7和0.8±0.6h;AUC0-t分别为105±71、272±81和396±93ng·h·ml-1;犬灌胃1、2、4mg·kg-19硝基喜树碱,Cmax分别为9.3±8.2、42.2±35.7和63.6±5.9ng·ml-1,Tmax分别为0.3±0.1、0.2±0.1、0.4±0.1h,t12分别为1.9±1.3、1.0±0.6和2.8±1.5h,AUC0-t分别为8.9±7.2、16.3±12.3和59.5±25.5ng·h·ml-1;各剂量组t12及ke与剂量无关(P>0.05);口服生物利用度<6%。结论:静脉及灌胃给药后,9硝基喜树碱在犬体内的动力学过程符合二室模型,在本实验所用的剂量范围内为线性动力学过程。9硝基喜树碱灌胃给药后吸收迅速,口服生物利用度低。

AIM： To study the pharmacokinetics of 9-nitro-camptothecin （ 9-NC ） in dogs. METHODS：Each Beagle dog was given a single dose of 9-NC by iv or ig administration. The concentrations of 9-NC in plasma were detected by HPIE and HPLC-MS. Pharmacokinetic parameters were determined from the plasma concentration-time data with the 3P97 software package. The relationships between AUC, Cmax or ke and dose were evaluated by linear regression. RESULTS： After iv administration of 9-NC at the dose of 0.5, 1, and 2 mg·kg%-1, the t1/2 values of 9-NC were 2.2 ± 2.2, 1.8 ± 1.7 and 0.8 ± 0.6 h, respectively, and AUC0-1, were 105 ± 71, 272 ± 81 and 396 ±93 ng·h·ml^-1 , respectively. After ig administration of 9-NC at the dose of l, 2, and 4 mg·kg^-1, 9-NC was rapidly absorbed, reaching Cmax of 9.3 ± 8.2, 42±36 and 64±6 ng·ml^-1 at Tmax, of 0.3±0.1, 0.2±0.1, 0.4 ± 0.1 h, respectively, the tin values of 9-NCwere 1.9 ± 1.3, 1.0 ± 0.6 and 2.8 ± 1.5 h, respectively, and AUC0-1 were 8.9±7.2, 16＋ 12 and 60±26 ng· h· ml^-1 , respeetively. The values of t1/2 and ke of 9- NC were independent of dose （ P 〉 0.05）. The absolute oral bioavailability of 9-NC was less than 6%. CONCLUSION： After iv or ig administration of 9-NC, the time eourse of plasma eoneentmtion in dogs eomplies with a two-eompartment model. The kinetie process of 9-NC in dogs is linear in the range of the experimental dosage. 9- NC is absorbed rapidly after ig administration and the oral bioavailability is poor.