PLASMA PHARMACOKINETICS AND TISSUE DISTRIBUTION OF PACLITAXEL IN CD2F1 MICE
PLASMA PHARMACOKINETICS AND TISSUE DISTRIBUTION OF PACLITAXEL IN CD2F1 MICE
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DOI：
10.1007/bf00685656
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发表时间：
1994-09-01
影响因子：
3
通讯作者：
EGORIN, MJ
中科院分区：
文献类型：
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作者：
EISEMAN, JL;EDDINGTON, ND;EGORIN, MJ
我们定义了紫杉醇在i.五，i.p.，p.o.，和s. C.向CD 2F 1小鼠施用22.5mg/kg。在i.静脉推注剂量为11.25 mg/kg或连续静脉输注3小时，输注速率为43.24 μ g/kg（-1）min（-1）。在给药后5 min至40 h之间采集血浆样本。以22.5 mg/kg剂量静脉给药后，对脑、心脏、肺、肝脏、肾脏、骨骼肌和睾丸（如适用）进行采样。采用液-液萃取，然后采用等度高效液相色谱法（HPLC）和紫外检测器测定血浆和组织中的紫杉醇浓度。静脉注射给药后，紫杉醇清除率（CL（tb））为3.25 ml min（-1）kg（-1），终末半衰期（t（1/2））为69 min。紫杉醇的CL（tb）为4.54 ml min（-1）kg（-1），终末t（1/2）为43 min。p.的情况下，p.o.，和s.c.行政分别。当以小体积递送药物以模拟用于评价体内抗肿瘤疗效的递送方法时，或当以大体积递送药物以模拟使用i. p.局部治疗的临床方案时，i. p.给药后的紫杉醇生物利用度相同。在Klucel：Tween 80中作为悬浮液腹膜内给药后，在小鼠血浆中未检测到紫杉醇。i.药代动力学参数相似。静脉输注22.5和11.25 mg/kg紫杉醇;然而，这些研究中计算的CL（tb）远低于3小时连续静脉输注相关值。静脉给药后，紫杉醇广泛分布于除脑和睾丸外的所有组织。这些数据有助于解释紫杉醇的临床前疗效研究，并通过缩放技术预测人体药代动力学。
We defined the pharmacokinetics of paclitaxel after i. v., i.p., p. o., and s. c. administration of 22.5 mg/kg to CD2F1 mice. Additional mice were studied after i. v. bolus dosing at 11.25 mg/kg or 3-h continuous i.v. infusions delivered at 43.24 mu g kg(-1) min(-1). Plasma was sampled between 5 min and 40 h after dosing. Brains, hearts, lungs, livers, kidneys, skeletal muscles, and, where applicable, testicles were sampled after i.v. dosing at 22.5 mg/kg. Liquid-liquid extraction followed by isocratic high-performance liquid chromatography (HPLC) with UV detection was used to determine paclitaxel concentrations in plasma and tissues. After i.v. administration to male mice, paclitaxel clearance (CL(tb)) was 3.25 ml min(-1) kg(-1) and the terminal half-life (t(1/2)) was 69 min. After i. v. administration to female mice, paclitaxel CL(tb) was 4.54 ml min(-1) kg(-1) and the terminal t(1/2) was 43 min. The bioavailability of paclitaxel was similar to 10%, 0, and 0 after i. p., p.o., and s.c. administration, respectively. Paclitaxel bioavailability after i.p. administration was the same when the drug was delivered in a small volume to mimic the delivery method used to evaluate in vivo antitumor efficacy or when it was delivered in a large volume to simulate clinical protocols using i.p. regional therapy. Paclitaxel was not detected in the plasma of mice after i.p. delivery of the drug as a sus pension in Klucel:Tween 80. Pharmacokinetic parameters were similar after i. v. delivery of paclitaxel at 22.5 and 11.25 mg/kg; however, the CL(tb) calculated in these studies was much lower than that associated with 3-h continuous i.v. infusions. After i.v. administration, paclitaxel was distributed extensively to all tissues but the brain and testicle. These data are useful in interpreting preclinical efficacy studies of paclitaxel and predicting human pharmacokinetics through scaling techniques.