Taurine conjugation of ibuprofen in humans and in rat liver in vitro. Relationship to metabolic chiral inversion.
Taurine conjugation of ibuprofen in humans and in rat liver in vitro. Relationship to metabolic chiral inversion.
复制标题
体外人类和大鼠肝脏中布洛芬的牛磺酸缀合。
DOI：
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发表时间：
1994
影响因子：
3.5
通讯作者：
T. Baillie
中科院分区：
文献类型：
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作者：
M. Shirley;X. Guan;D. Kaiser;G. Halstead;T. Baillie
在向人类单次口服剂量（400 mg）或RS-布洛芬（RS-IBP）后，从尿液中分离出一种新的代谢物，并通过串联质谱法鉴定为IBP的牛磺酸缀合物（IBP-Tau）。寻找了相应的甘氨酸缀合物，但在这些研究中未检出。定量分析表明，牛磺酸结合代表了IBP的次要生物转化途径（24 h内剂量的1.52 +/- 0.43%，n = 4），但它仍然是一种重要的机制，因为它需要事先形成IBP的辅酶A硫酯（IBP-CoA）。后一种缀合物，由于其细胞内区室化而未在体内检测到，在R-至S-IBP的代谢手性转化中起关键作用。通过立体选择性气相色谱-质谱法，发现在非外消旋条件下从尿IBP-Tau中释放的IBP主要由（约1000 μ mol/L）组成。87%）的分子为S构型。从给予药物的假外消旋混合物（R-IBP/S-[2 H3]IBP）的志愿者的单独实验中，显示大部分S-IBP-Tau通过手性转化衍生自S-IBP，而不是R-IBP。这些发现，连同大鼠肝脏线粒体制剂和离体大鼠肝细胞的体外实验结果，表明虽然IBP活化为CoA硫酯有利于R对映体，但S-IBP也参与CoA依赖性反应，包括代谢手性转化。
Following administration of a single oral dose (400 mg) or RS-ibuprofen (RS-IBP) to humans, a novel metabolite was isolated from urine and identified by tandem mass spectrometry as the taurine conjugate of IBP (IBP-Tau). The corresponding glycine conjugate was sought but was not detected in these studies. Quantitative analyses indicated that taurine conjugation represents a minor biotransformation pathway for IBP (1.52 +/- 0.43% of the dose over 24 h, n = 4), but it is nonetheless one of mechanistic significance in that it requires the prior formation of the coenzyme A thioester of IBP (IBP-CoA). The latter conjugate, which has not been detected in vivo because of its intracellular compartmentalization, plays a key role in the metabolic chiral inversion of R- to S-IBP. By means of stereoselective gas chromatography-mass spectrometry, it was found that IBP liberated from the urinary IBP-Tau under nonracemizing conditions consisted mainly (ca. 87%) of molecules of S configuration. From separate experiments with volunteers given a pseudoracemic mixture of the drug (R-IBP/S-[2H3]IBP), it was shown that the majority of the S-IBP-Tau was derived from S-IBP, rather than from R-IBP by way of chiral inversion. These findings, together with the results of in vitro experiments with rat liver mitochondrial preparations and isolated rat hepatocytes, demonstrate that although activation of IBP to its CoA thioester favors the R enantiomer over its antipode, S-IBP also participates in CoA-dependent reactions, including metabolic chiral inversion.