Tissue levels of WR-1065, the active metabolite of amifostine (Ethyol®), are equivalent following intravenous or subcutaneous administration in cynomolgus monkeys
Tissue levels of WR-1065, the active metabolite of amifostine (Ethyol®), are equivalent following intravenous or subcutaneous administration in cynomolgus monkeys
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DOI：
10.1159/000081316
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发表时间：
2004-01-01
期刊：
影响因子：
3.5
通讯作者：
Cassatt, DR
中科院分区：
文献类型：
--
作者：
Bachy, CM;Fazenbaker, CA;Cassatt, DR
氨磷汀（Ethyol（R））是一种细胞保护药物，被批准用于减少头颈部癌症患者接受术后放疗时的口干症。虽然氨磷汀被批准用于静脉输注，但标签外皮下给药途径已变得更加普遍。尽管人类患者数据表明，与皮下给药相比，静脉给药后活性代谢产物（WR-1065）的血浆生物利用度更高，但由于难以获得人体样本，因此没有相应的数据显示两种给药途径后WR-1065的人体组织水平。在我们的研究中，我们比较了两种给药途径后WR-1065在灵长类动物中的血浆和组织药代动力学。猴静脉或皮下注射260 mg/m2氨磷汀。通过反相高压液相色谱法（HPLC）和荧光检测法分析血浆样品中的总WR-1065，直至氨磷汀给药后4 h。在给药后30和60分钟，通过反相HPLC和电化学检测分析组织中的游离WR-1065。静脉内施用后，血浆WR-1065水平迅速达到峰值并显示出双指数下降，而皮下施用后WR-1065水平缓慢上升并指数下降。皮下给药WR-1065的相对血浆生物利用度在30和60分钟时较低。有趣的是，30分钟后，皮下给药后组织显示相等或略高的WR-1065浓度。两种途径给药后60 min后的水平相当。在灵长类动物中进行的血浆生物利用度研究证实了人血浆数据。扩大研究以评估WR-1065的灵长类动物组织水平揭示，尽管皮下给药后血浆生物利用度较低，但活性代谢物的组织水平令人惊讶地大于或等于在静脉内接受药物的动物中测量的水平。这些研究加强了皮下注射氨磷汀在放射肿瘤学中的应用。版权所有（C）2004 S. Karger AG，巴塞尔。
Amifostine (Ethyol(R)) is a cytoprotective drug approved for the reduction of xerostomia in head and neck cancer when administered to patients receiving postoperative radiation therapy. Although amifostine is approved for intravenous infusion, the off-label subcutaneous route of administration has become more prevalent. Although human patient data indicate higher plasma bioavailability of the active metabolite (WR-1065) following intravenous compared to subcutaneous administration, there are no corresponding data showing human tissue levels of WR-1065 following either route of administration due to the difficulty in obtaining human specimens. In our study we compared plasma and tissue pharmacokinetics of WR-1065 in primates following both routes of administration. Monkeys received amifostine at a dose of 260 mg/m(2) either intravenously or subcutaneously. Plasma samples were analyzed for total WR-1065 by reverse-phase high-pressure liquid chromatography (HPLC) and fluorescence detection up to 4 h after amifostine administration. Tissues were analyzed for free WR-1065 by reverse-phase HPLC and electrochemical detection 30 and 60 min after administration. Following intravenous administration, plasma WR-1065 levels peaked rapidly and showed a bi-exponential decline, while following subcutaneous administration WR-1065 levels rose slowly and declined exponentially. The relative plasma bioavailability of WR-1065 given subcutaneously was lower at 30 and 60 min. Interestingly, after 30 min, tissues showed equal or slightly greater concentrations of WR-1065 following subcutaneous administration. Levels following 60 min were comparable following both routes. The plasma bioavailability studies performed in primates confirm human plasma data. Expanding the study to evaluate primate tissue levels of WR-1065 revealed that despite lower plasma bioavailability following subcutaneous administration, tissue levels of the active metabolite were surprisingly greater than or equal to those measured in animals that received the drug intravenously. These studies strengthen the argument for subcutaneous administration of amifostine in radiation oncology. Copyright (C) 2004 S. Karger AG, Basel.