Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA.
Chem Res Toxicol. 2011 Dec 19;24(12):2109-14. doi: 10.1021/tx2004147. Epub 2011 Nov 17.
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. Upon the basis of 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.
利托那韦增强的蛋白酶抑制剂方案被广泛用于 HIV 化疗。然而，利托那韦会引起多种副作用，其机制尚未完全阐明。本研究旨在探索可能与利托那韦毒性相关的利托那韦代谢途径。代谢组学分析筛选出了小鼠体内的 26 种利托那韦代谢物，其中一半是新的。这些新的利托那韦代谢物包括两种甘氨酸结合物、两种 N-乙酰半胱氨酸结合物和三种开环产物。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。基于这些新代谢物的结构，提出了五种生物活化途径，可能与硫酸化和环氧化有关。通过使用 Cyp3a 基因敲除小鼠，我们证实 CYP3A 参与了利托那韦生物活化的四条途径。此外，在人肝微粒体中孵育利托那韦时，这五种生物活化途径都得到了重现。进一步的研究建议确定 CYP3A 和这些生物活化途径在利托那韦毒性中的作用。
