Disposition of WR-1065 in the liver of tumor-bearing rats following regional vs systemic administration of amifostine.
Disposition of WR-1065 in the liver of tumor-bearing rats following regional vs systemic administration of amifostine.
复制标题
局部与全身给予氨磷汀后，WR-1065 在荷瘤大鼠肝脏中的分布。
DOI：
10.1002/bdd.380
复制
发表时间：
2004
影响因子：
2.1
通讯作者：
Smith,DavidE
中科院分区：
文献类型：
--
作者：
Levi,Micha;DeRemer,SusanJ;Dou,Chunzhi;Ensminger,WilliamD;Smith,DavidE
目的-氨磷汀是一种前药，其选择性主要取决于膜结合碱性磷酸酶活性差异导致的正常组织中细胞保护代谢产物WR-1065的优先形成和摄取。据推测，氨磷汀可能是一个很好的候选人区域药物输送到肝脏，因为它的大的肝脏提取和全身clearance. Methods大鼠肝脏植入步行者-256肿瘤。荷瘤大鼠通过门静脉或股静脉输注氨磷汀（200 mg/kg）15 min。WR-1065在血液、肝脏和肿瘤中的浓度在不同时间进行测量。结果-WR-1065肿瘤门静脉给药AUC 15 − 60为全身给药的40%，门静脉给药后的肿瘤浓度为全身给药后的五分之一。门静脉给药WR-1065肝脏AUC 15 - 60比全身给药值高60%。WR-1065经门静脉给药后的肝脏/肿瘤浓度比是全身给药后的8倍。不幸的是，全身暴露于WR-1065是更大的门静脉与全身amifostine. Conclusions氨磷汀可能会提供更多的肝脏保护和减少肿瘤保护从放疗或化疗时，通过门静脉给药。然而，门静脉给药也会增加WR-1065的全身暴露，这与低血压相关。版权所有© 2004年约翰威利父子有限公司。
Purpose—Amifostine is a prodrug in which selectivity is largely determined by the preferential formation and uptake of its cytoprotective metabolite, WR‐1065, in normal tissues as a result of differences in membrane‐bound alkaline phosphatase activity. It was hypothesized that amifostine may be a good candidate for regional drug delivery to the liver because of its large hepatic extraction and total body clearance.Methods—Rat livers were implanted with Walker‐256 tumors. The tumor‐bearing rats received 15 min infusions of amifostine (200 mg/kg) via the portal vein or the femoral vein. WR‐1065 concentrations in the blood, liver and tumor were measured at various times.Results—The WR‐1065 tumor portal dosingAUC15−60was 40% of systemic dosing, and tumor concentrations following portal dosing were one‐fifth of that following systemic dosing. The portal dosing WR‐1065 liverAUC15−60was 60% higher than the values for systemic dosing. The liver/tumor concentration ratios of WR‐1065 following portal dosing were up to 8‐fold higher than the ratio following systemic administration. Unfortunately, systemic exposure to WR‐1065 was greater following portal vs systemic amifostine.Conclusions—Amifostine may provide increased liver protection and decreased tumor protection from radio‐ or chemotherapy when administered by the portal vein. However, portal dosing also increases systemic exposure to WR‐1065, which is associated with hypotension. Copyright © 2004 John Wiley & Sons, Ltd.