鱼藤素（一种大鼠癌症化学预防剂）的药代动力学

Pharmacokinetics of deguelin, a cancer chemopreventive agent in rats.

作者信息

Udeani G O, Zhao G M, Shin Y G, Kosmeder J W, Beecher C W, Kinghorn A D, Moriarty R M, Moon R C, Pezzuto J M

机构信息

Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612-7230, USA.

出版信息

Cancer Chemother Pharmacol. 2001 Mar;47(3):263-8. doi: 10.1007/s002800000187.

DOI:10.1007/s002800000187

PMID:11320671

Abstract

PURPOSE

To study the pharmacokinetics of deguelin, a naturally occurring potential cancer chemopreventive agent, in rats.

METHODS

[3H]Deguelin was administered intravenously (i.v.) under anesthesia, and blood samples were collected over 24 h. [3H]Deguelin and metabolites were extracted from plasma with ethyl acetate, and quantified by HPLC. Data were analyzed with the WinNolin pharmacokinetic software package to determine pharmacokinetic parameters. A three-compartment first-order elimination model was used to fit the plasma concentration-time curve. In addition, deguelin concentrations in tissues after i.v. and intragastric (i.g.) administration were determined by HPLC, and excretion (feces and urine) was evaluated over a 5-day period after i.g. administration.

RESULTS

Deguelin exhibited a mean residence time (MRT) of 6.98 h and terminal half-life (t1/2(gamma)) of 9.26 h. The area under the curve (AUC) and total clearance (Cl) were 57.3 ng.h/ml and 4.37 l/h per kg, respectively, with an apparent volume of distribution (V) and volume of distribution at steady-state (Vss) of 3.421 l/kg and 30.46 l/kg, respectively. Following i.v. administration, the relative levels of tissue distribution were as follows: heart > fat > mammary gland > colon > liver > kidney > brain > lung. Following i.g. administration, the relative levels of tissue distribution were as follows: perirenal fat > heart > mammary gland > colon > kidney > liver > lung > brain > skin. Within 5 days of i.g. administration, about 58.1% of the [3H]deguelin was eliminated via the feces and 14.4% via the urine. Approximately 1.7% of unchanged deguelin was found in the feces, and 0.4% in the urine.

CONCLUSIONS

An initial pharmacokinetic investigation of deguelin showed that this rotenoid has a relatively long MRT and half-life in plasma in the rat. The compound distributed in the tissues and excreted as metabolites, mainly via the feces.

摘要

目的

研究天然存在的潜在癌症化学预防剂鱼藤素在大鼠体内的药代动力学。

方法

在麻醉状态下静脉注射[³H]鱼藤素，在24小时内采集血样。用乙酸乙酯从血浆中提取[³H]鱼藤素及其代谢物，并用高效液相色谱法进行定量分析。使用WinNolin药代动力学软件包分析数据，以确定药代动力学参数。采用三室一级消除模型拟合血浆浓度-时间曲线。此外，通过高效液相色谱法测定静脉注射和灌胃给药后组织中的鱼藤素浓度，并在灌胃给药后5天内评估排泄情况（粪便和尿液）。

结果

鱼藤素的平均驻留时间（MRT）为6.98小时，末端半衰期（t1/2(γ)）为9.26小时。曲线下面积（AUC）和总清除率（Cl）分别为57.3 ng·h/ml和4.37 l/h per kg，表观分布容积（V）和稳态分布容积（Vss）分别为3.421 l/kg和30.46 l/kg。静脉注射后，组织分布的相对水平如下：心脏＞脂肪＞乳腺＞结肠＞肝脏＞肾脏＞脑＞肺。灌胃给药后，组织分布的相对水平如下：肾周脂肪＞心脏＞乳腺＞结肠＞肾脏＞肝脏＞肺＞脑＞皮肤。灌胃给药后5天内，约58.1%的[³H]鱼藤素通过粪便排出，14.4%通过尿液排出。粪便中约1.7%为未改变的鱼藤素，尿液中为0.4%。