萨力多胺的临床药理学。

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埃里克森T, Bjorkman年代,霍格伦德P

萨力多胺的临床药理学。

欧元中国新药杂志。2001年8月,57 (5):365 - 76。doi: 10.1007 / s002280100320。

PubMed ID
11599654 (在PubMed
]
文摘

背景:萨力多胺一个手性中心,和外消旋体的(R) - (S)介绍了萨力多胺作为镇静药物在1950年代末。在1961年,它被撤回由于致畸性和神经病变。现在有越来越多的临床兴趣萨力多胺由于其独特的抗炎和免疫调节作用。目的:批判性的药代动力学研究并简要回顾药效学的影响和对萨力多胺的研究在考虑其化学和立体化学性质和新陈代谢。方法:文献检索和药物动力学的计算机模拟。必威国际app结果:合理使用萨力多胺是有问题由于缺乏基础知识的作用机理,分离对映体和代谢物的影响和剂量,浓度效应关系。由于其抑制肿瘤坏死因子-α和血管生成,外消旋萨力多胺试验中得到了良好的效果在各种皮肤和黏膜疾病,克罗恩病、移植物抗宿主病,并发症人类免疫缺陷病毒,最近,在多发性骨髓瘤。相关的不良反应通常是镇静的效果。不可逆转的有毒周围神经病变和胎儿畸形是严重的并发症是可以预防的。发表的一些药代动力学研究的结果可以质疑由于贫穷的方法和不定向分析的使用。 The enantiomers of thalidomide undergo spontaneous hydrolysis and fast chiral interconversion at physiological pH. The oral bioavailability of thalidomide has not been unequivocally determined, but available data suggest that it is high. Absorption is slow, with a time to maximum plasma concentration of at least 2 h, and may also be dose-dependent; however, that of the separate enantiomers may be faster due to higher aqueous solubility. Estimation of the volume of distribution is complicated by probable hydrolysis and chiral inversion also in peripheral compartments. A value of around 11/kg is however plausible. Plasma protein binding is low with little difference between the enantiomers. Elimination of thalidomide is mainly by pH-dependent spontaneous hydrolysis in all body fluids with an apparent mean clearance of 10 l/h for the (R)- and 21 l/h for the (S)-enantiomer in adult subjects. Blood concentrations of the (R)-enantiomer are consequently higher than those of the (S)-enantiomer at pseudoequilibrium. The mean elimination half-life of both enantiomers is 5 h. One hydroxylated metabolite has been found in low concentrations in the blood. Since both enzymatic metabolism and renal excretion play minor roles in the elimination of thalidomide, the risk of drug interactions seems to be low. CONCLUSIONS: The interest in and use of thalidomide is increasing due to its potential as an immunomodulating and antiangiogenic agent. The inter-individual variability in distribution and elimination is low. Apart from this, its use is complicated by the lack of knowledge of dose- or concentration-effect relationships, possible dose-dependent oral absorption and of course by its well-known serious adverse effects.

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