铟-111-二乙烯三胺五乙酸-D-苯丙氨酸1-奥曲肽体内可溶性代谢物的鉴定。

Identification of the soluble in vivo metabolites of indium-111-diethylenetriaminepentaacetic acid-D-Phe1-octreotide.

作者信息

Bass L A, Lanahan M V, Duncan J R, Erion J L, Srinivasan A, Schmidt M A, Anderson C J

机构信息

Division of Radiological Sciences, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

出版信息

Bioconjug Chem. 1998 Mar-Apr;9(2):192-200. doi: 10.1021/bc970158h.

DOI:10.1021/bc970158h

PMID:9548534

Abstract

Indium-111-diethylenetriaminepentaacetic Acid-D-phenylalanine-octreotide ([111]In-DTPA-octreotide) is a cyclic eight amino acid somatostatin analogue which is approved for gamma scintigraphy of neuroendocrine tumors. To address the factors that contribute to liver and kidney retention of this radiopharmaceutical, its metabolism was evaluated in normal and tumor-bearing rats. The soluble fractions from nontarget (liver and kidney) and target (tumor, pancreas, adrenals) organ homogenates were analyzed out to 21 h postinjection, and urine was analyzed out to 12 h postinjection. The blood was analyzed at shorter time intervals due to the rapid clearance of (111)In-DTPA-octreotide. Radio-TLC and HPLC were used to analyze organ homogenates, blood, and urine. By TLC, intact (111)In-DTPA-octreotide was resolved from the soluble metabolites, and a similar apparent rate of metabolism was observed in the liver, kidney, tumor, and pancreas with approximately 30% intact (111)In-DTPA-octreotide at 4 h postinjection. In the adrenals, metabolism occurred more slowly with approximately 60% intact (111)In-DTPAoctreotide at 4 h postinjection. At 4 h postinjection, the activity excreted in the urine consisted of 85% intact (111)In-DTPA-octreotide. HPLC provided resolution of the individual extractable metabolites. In an attempt to identify these metabolites, two DTPA-amino acid sequences were synthesized: DTPA-D-Phe-Cys and DTPA-D-Phe. Under the conditions used for metabolite analysis, (111)In-DTPA-D-Phe-Cys-OH eluted at 14.6 min and (111)In-DTPA-D-Phe-OH eluted at 7.0 min. Each of these standard sequences was combined with the soluble portion of the organ homogenate and was shown by HPLC to coelute with the metabolites. These data suggest that (111)In-DTPA-octreotide was initially degraded to (111)In-DTPA-D-Phe-Cys-OH and (111)In-DTPA-D-Phe-OH. The (111)In-DTPA-D-Phe-Cys-OH was further degraded to (111)In-DTPA-D-Phe-OH, which appeared to be the final metabolite that was extracted from the organs. From these results, it can be concluded that at longer time points (> 2 h postinjection) a significant amount of (111)In was retained in nontarget organs as (111)In-DTPA-D-Phe-OH and (111)In-DTPA-D-Phe-Cys-OH and not as intact (111)In-DTPA-octreotide.

摘要

铟-111-二乙烯三胺五乙酸-D-苯丙氨酸-奥曲肽（[111]In-DTPA-奥曲肽）是一种环状八氨基酸生长抑素类似物，已被批准用于神经内分泌肿瘤的γ闪烁显像。为了探究导致这种放射性药物在肝脏和肾脏潴留的因素，在正常大鼠和荷瘤大鼠中对其代谢情况进行了评估。在注射后21小时内对非靶器官（肝脏和肾脏）及靶器官（肿瘤、胰腺、肾上腺）匀浆的可溶部分进行分析，在注射后12小时内对尿液进行分析。由于（111）In-DTPA-奥曲肽清除迅速，所以对血液在更短的时间间隔进行分析。采用放射性薄层层析法（Radio-TLC）和高效液相色谱法（HPLC）对器官匀浆、血液和尿液进行分析。通过薄层层析法，可将完整的（111）In-DTPA-奥曲肽与可溶代谢产物分离，在肝脏、肾脏、肿瘤和胰腺中观察到类似的代谢表观速率，注射后4小时约30%为完整的（111）In-DTPA-奥曲肽。在肾上腺中，代谢发生得较为缓慢，注射后4小时约60%为完整的（111）In-DTPA奥曲肽。注射后4小时，尿液中排出的活性成分85%为完整的（111）In-DTPA-奥曲肽。高效液相色谱法可分离出各个可提取的代谢产物。为了鉴定这些代谢产物，合成了两个DTPA-氨基酸序列：DTPA-D-苯丙氨酸-半胱氨酸和DTPA-D-苯丙氨酸。在用于代谢产物分析的条件下，（111）In-DTPA-D-苯丙氨酸-半胱氨酸-OH在14.6分钟洗脱，（111）In-DTPA-D-苯丙氨酸-OH在7.0分钟洗脱。将这些标准序列中的每一个与器官匀浆的可溶部分混合，通过高效液相色谱法显示它们与代谢产物共洗脱。这些数据表明，（111）In-DTPA-奥曲肽最初降解为（111）In-DTPA-D-苯丙氨酸-半胱氨酸-OH和（111）In-DTPA-D-苯丙氨酸-OH。（111）In-DTPA-D-苯丙氨酸-半胱氨酸-OH进一步降解为（111）In-DTPA-D-苯丙氨酸-OH，这似乎是从器官中提取的最终代谢产物。从这些结果可以得出结论，在较长时间点（注射后>2小时），大量的（111）In以（111）In-DTPA-D-苯丙氨酸-OH和（111）In-DTPA-D-苯丙氨酸-半胱氨酸-OH的形式潴留于非靶器官，而非完整的（111）In-DTPA-奥曲肽。