Metabolomic screening and identification of the bioactivation pathways of ritonavir.
Metabolomic screening and identification of the bioactivation pathways of ritonavir.
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DOI：
10.1021/tx2004147
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发表时间：
2011-12-19
影响因子：
4.1
通讯作者：
Ma X
中科院分区：
文献类型：
--
作者：
Li F;Lu J;Ma X
利托那韦增强的蛋白酶抑制剂方案广泛用于 HIV 化疗。然而，利托那韦会引起多种副作用，且其机制尚不完全清楚。本研究旨在探索利托那韦可能与其毒性相关的代谢途径。代谢组学分析在小鼠体内筛选出26种利托那韦代谢物，其中一半是新的。这些新型利托那韦代谢物包括两种甘氨酸缀合产物、两种N-乙酰半胱氨酸缀合产物和三种开环产物。伴随着利托那韦开环代谢物的产生，预计会形成甲硫酰胺和2-甲基丙硫酰胺。根据这些新代谢物的结构，提出了五种生物活化途径，它们可能与硫酸化和环氧化有关。通过使用 Cyp3a 缺失小鼠，我们证实 CYP3A 参与 RTV 生物激活的四种途径。此外，所有这五种生物激活途径都在利托那韦在人肝微粒体中的孵育中得到了重现。建议进一步研究以确定 CYP3A 和这些生物激活途径在利托那韦毒性中的作用。
Ritonavir-boosted protease inhibitor regimens are widely used for HIV chemotherapy. However, ritonavir causes multiple side effects, and the mechanisms are not fully understood. The current study was designed to explore the metabolic pathways of ritonavir that may be related to its toxicity. Metabolomic analysis screened out 26 ritonavir metabolites in mice, and half of them are novel. These novel ritonavir metabolites include two glycine conjugated, two N-acetylcysteine conjugated and three ring-open products. Accompanied with the generation of ritonavir ring-open metabolites, the formation of methanethioamide and 2-methylpropanethioamide were expected. Based upon the structures of these novel metabolites, five bioactivation pathways are proposed, which may be associated with sulfation and epoxidation. By using Cyp3a-null mice, we confirmed that CYP3A is involved in four pathways of RTV bioactivation. In addition, all these five bioactivation pathways were recapitulated in the incubation of ritonavir in human liver microsomes. Further studies are suggested to determine the role of CYP3A and these bioactivation pathways in ritonavir toxicity.
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影响因子：
4.1
作者：
Gangl, E;Utkin, I;Vouros, P
通讯作者：
Vouros, P
影响因子：
5.4
作者：
MARKOWITZ, M;MO, HM;HO, DD
通讯作者：
HO, DD
DOI：
10.1097/qai.0b013e318189a7df
发表时间：
2009-03-01
期刊：
Journal of acquired immune deficiency syndromes (1999)
影响因子：
--
作者：
Haas DW;Koletar SL;Laughlin L;Kendall MA;Suckow C;Gerber JG;Zolopa AR;Bertz R;Child MJ;Hosey L;Alston-Smith B;Acosta EP;A5213 StudyTeam
通讯作者：
A5213 StudyTeam
影响因子：
3.8
作者：
Merry, C;Barry, MG;Back, DJ
通讯作者：
Back, DJ
影响因子：
4.1
作者：
MIZUTANI, T;YOSHIDA, K;KAWAZOE, S
通讯作者：
KAWAZOE, S