Hydroxylated metabolites of Thalidomide:: Formation in-vitro and in-vivo in man
Hydroxylated metabolites of Thalidomide:: Formation in-vitro and in-vivo in man
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DOI：
10.1111/j.2042-7158.1998.tb03368.x
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发表时间：
1998-12-01
影响因子：
3.3
通讯作者：
Höglund, P
中科院分区：
文献类型：
--
作者：
Eriksson, T;Björkman, S;Höglund, P
由于沙利度胺独特的免疫调节作用，人们对沙利度胺的临床应用重新产生了兴趣。由于沙利度胺在人体中的代谢数据非常稀少，本研究的目的是开发沙利度胺的 5-羟基、5,6-二羟基、4,5-二羟基和 5'-羟基代谢物的 HPLC 测定法，并研究它们在体外肝匀浆中和健康志愿者体内可能形成的情况。开发了具有 UV 检测的反相 HPLC 测定法，用于定量代谢物在血浆和孵育样品中处于低 ng mL(-1) 范围内。研究了代谢物的稳定性，并通过快速冷却和酸化样品来避免降解。将沙利度胺与来自人肝脏的 S9 级分一起孵育后，可以证明 5-羟基和 5'-羟基代谢物的形成。发现了低浓度的 5'-羟基代谢物；来自八名口服沙利度胺的健康男性志愿者的血浆样本。其他三种代谢物HPLC未检出，检出限为1-2 ng mL(-1)。由此证明沙利度胺在人肝脏中形成两种羟基化代谢物，但在循环中仅检测到其中一种。
There is renewed interest in the clinical use of thalidomide, because of its unique immunomodulating action. Because data on the metabolism of thalidomide in man are very sparse, the aim of this study was to develop HPLC assays for the 5-hydroxy, 5,6-dihydroxy, 4,5-dihydroxy and 5'-hydroxy metabolites of thalidomide and to investigate their possible formation in man-in-vitro in liver homogenates and in-vivo in healthy volunteers.Reversed-phase HPLC assays with UV detection were developed for quantification of the metabolites in the low ng mL(-1) range in plasma and incubate samples. The stability of the metabolites was investigated and degradation was avoided by rapid chilling and acidification of the samples. After incubation of thalidomide with fraction S9 from human liver, formation of the 5-hydroxy and 5'-hydroxy metabolites could be demonstrated. The 5'-hydroxy metabolite was found, in low concentrations; in plasma samples from eight healthy male volunteers who had received thalidomide orally. The other three metabolites could not be found by HPLC with detection limits of 1-2 ng mL(-1).Thus the formation of two hydroxylated metabolites of thalidomide in the liver in man was demonstrated, but only one of these could be detected in the circulation.