Analytical and pharmacokinetic studies with 5-chloro-2′-deoxycytidine
Analytical and pharmacokinetic studies with 5-chloro-2′-deoxycytidine
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DOI：
10.1016/s0006-2952(02)01413-2
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发表时间：
2002-11-15
影响因子：
5.8
通讯作者：
McCormack, JJ
中科院分区：
文献类型：
--
作者：
Hale, JT;Bigelow, JC;McCormack, JJ
5-氯-2‘-脱氧胞苷(NSC 371331，CDC)是一种可能用于癌症治疗的放射增敏剂。以前的研究已经证明了CDC在体内的有效性，并对其代谢进行了各种调节。本文描述了我们的临床前研究，以确定CDC的药代动力学特性和药物在单独和代谢调节剂四氢尿苷(清华)存在下的药物处置。四氢尿苷是一种胞苷脱氨酶抑制剂。采用高效液相色谱法，色谱柱为C-18柱，以三氟乙酸水溶液和乙腈为溶剂进行梯度洗脱，在290 nm处检测。样品在进样前用硫酸铵处理，然后进入高效液相色谱系统。CDC在水溶液和小鼠血浆中均稳定。大剂量CDC(100 mg/kg)静脉注射。或者IP。给小鼠测定CDC血浆半衰期(10min)。口服给药后血浆中未检出CDC。它被胞苷脱氨酶迅速转化为5-氯-2‘-脱氧尿苷(CDU)，在静脉注射后采集的血浆和尿样中很容易检测到CDU。和IP。疾病预防控制中心的管理。当CDC剂量从5 mg/kg到100 mg/kg与清华100 mg/kg一起给药时，CDC水平升高。CDC通过肾脏和酶脱氨作用被消除，并且不与血浆蛋白结合。用分离的酶体外测定CDC代谢途径的初始步骤。小鼠肾脏胞苷脱氨酶将CDC转化为CDU，胸苷磷酸化酶将CDU转化为5-氯尿嘧啶(5-CU)。这些研究的结论是：(A)CDC是一种半衰期短的药物，(B)它通过肾脏排泄，主要以代谢产物的形式存在。清华给药显著增加了小鼠血浆中CDC的浓度，支持清华与CDC合用应在临床试验中进行评估的建议。(C)2002 Elsevier Science Inc.保留所有权利。
5-Chloro-2'-deoxycytidine (NSC 371331, CDC) is in development as a possible radiosensitizing agent for cancer treatment. Previous studies have been done to demonstrate the in vivo efficacy of CDC with various modulators of its metabolism. This paper describes our preclinical studies to determine the pharmacokinetic properties of CDC and the disposition of the drug, both alone and in the presence of the metabolic modulator tetrahydrouridine (THU), a cytidine deaminase inhibitor. Detection of the drug in biological fluids was performed by HPLC analysis using a C-18 column, gradient elution with solvents composed of aqueous trifluoroacetic acid and acetonitrile, and ultraviolet absorbance at 290 nm. Samples were processed by treatment with ammonium sulfate prior to injection into the HPLC system. CDC was stable in aqueous solution and in mouse plasma. High doses of CDC (100 mg/kg) were given i.v. or i.p. to mice for the determination of CDC plasma half-life (10 min). CDC was not detectable in plasma after oral administration. It was converted rapidly to 5-chloro-2'-deoxyuridine (CDU) by cytidine deaminase, and CDU was readily discernable in plasma and urine samples collected after i.v. and i.p. administration of CDC. When CDC in doses ranging from 5 to 100 mg/kg was given with 100 mg/kg of THU, increased plasma levels of CDC were seen. CDC was eliminated through the kidneys, as well as by enzymatic deamination, and did not bind to plasma proteins. The initial steps of the CDC metabolic pathway were determined in vitro with isolated enzymes. Cytidine deaminase from mouse kidney converted CDC into CDU; thymidine phosphorylase converted CDU into 5-chlorouracil (5-CU). The conclusions of these studies are: (a) CDC is a drug with a short half-life and (b) it is excreted through the kidney, mainly in metabolite form. Administration of THU substantially increased the concentrations of CDC in mouse plasma, supporting proposals that the combination of THU with CDC should be evaluated in clinical trials. (C) 2002 Elsevier Science Inc. All rights reserved.