吳美環2006-07-262018-07-112006-07-262018-07-112004http://ntur.lib.ntu.edu.tw//handle/246246/22894三氧化砷靜脈注射是最新且有效的治 療方法，但其可能之毒性資料仍有限。本 研究探討其藥理動態指標及組織各代謝物 之濃度變化。主要之發現如下： 一、 實驗兔接受靜脈三氧化砷單一劑量 （0.2、0.6 或1.5mg/kg）之表現： 血液中主要為As（III），且在 1.5mg/kg 劑量呈現代謝之限值。而組 織中，DMA 為主要的成分。而As （III），DMA 與MMA 濃度與劑量之 曲線呈 線性變化。 二、實驗兔接受靜脈三氧化砷30 天每天注 射後之表現： 長期給藥後可能誘發部分組織對 砷化合物之代謝能力，例如在kidney 其As（III）下降且DMA 增加。此外， 在liver DMA 原本濃度最高，但在30 天給藥後，其normalized 的組織濃度 變成non-linear 表示liver 在長期高劑 量給藥後，對DMA 代謝能力的增加。 三、長期給藥30 天後再停藥30 天後之實 驗兔表現： As（III），DMA 與MMA 在組織 之堆積大都可消除，但hair 中的As （III）與DMA，heart，lung 與kidney 劑量DMA 仍存在。 四、結論： 三氧化砷靜脈給藥單一或長期給 藥，其藥理動力學指標大致相同， 1.5mg/kg/dose 為其限值。組織主要之 代謝物為DMA，而停藥後組織內As （III），DMA 與MMA 大多可清除， 但仍有組織之選擇性。Parenteral administration of As2O3 has recently been recognized as an effective antineoplastic therapy, especially for the treatment of acute promyelocytic leukemia. Its efficacy and toxicity are concentration-dependent and are related to the fractions of different arsenic species and the degree of methylation. In this study, arsenic trioxide was given parenterally to rabbits as a single dose or as a daily dose (0.2, 0.6 and 1.5 mg/kg) for 30 days. The blood and organ concentrations of the arsenic species, including As(III), DMA and MMA, were studied on day-1 (single-dose study), day-30 (multiple dosing study) and day-60 (reversibility study). The results showed that As(III) was the major detectable arsenic species in the blood. The pharmacokinetic parameters (total clearance, area under the curve, etc) for As(III) indicated a limit for the capacity to eliminate As(III) at the dose of 1.5 mg/kg, and were quite the same after a single or chronic multiple dosing. In tissues, DMA was found to be the major metabolite and the concentrations of DMA, As(III), and MMA in general increased with the dose, with the increase most significant at a dose of 1.5 mg/kg. However, normalized tissue distribution of As(III) in the kidney on day-1, but not on day-30, was nonlinear. Along with decreased levels of As(III) and increased 2 levels of DMA, an inducible capacity of methylating As(III) to DMA after chronic dosing in kidney was suggested. The tissue concentration of DMA was highest in lung and liver, and the normalized tissue distributions in liver on day-30 were nonlinear, suggesting a limit in eliminating DMA after a chronic high load of As(III). Tissue concentrations of As(III), DMA and MMA in bladder increased dramatically after chronic dosing. However, after wash-out for 30 days, As(III), DMA and MMA were all undetectable in bladder and liver. But, As(III) in hair and low levels of DMA in lung, kidney, heart and hair were still detected. In conclusion, in rabbits we found a similar pharmacological profile after a single or chronic multiple dosing of parenteral arsenic trioxide, with a limiting metabolizing capacity at the dose of 1.5 mg/kg. Tissue accumulation of arsenic species, mainly DMA, and its reversibility after washout were tissue-selective. The potential for late toxicities of arsenic trioxide in organs with significant tendency for arsenic accumulation and low reversibility should be closely monitored.application/pdf48471 bytesapplication/pdfzh-TW國立臺灣大學醫學院小兒科三氧化砷砷代謝物藥理動力學arsenic trioxideheartMMADMAelectrophysiologyreporthttp://ntur.lib.ntu.edu.tw/bitstream/246246/22894/1/922314B002203.pdf