考比司他的生物转化：代谢途径与酶
Biotransformation of Cobicistat: Metabolic Pathways and Enzymes.
作者信息
Wang Pengcheng, Shehu Amina I, Liu Ke, Lu Jie, Ma Xiaochao
机构信息
309 Salk Pavilion, 335 Sutherland Drive, Pittsburgh, PA 15261, USA.
出版信息
Drug Metab Lett. 2016;10(2):111-23. doi: 10.2174/1872312810666160303112212.
BACKGROUND
Cobicistat (COBI) is a pharmacoenhancer for antiretroviral therapy.
OBJECTIVE
The current study was designed to profile the metabolic pathways of COBI and to determine the enzymes that contribute to COBI metabolism.
METHOD
We screened COBI metabolites in mice and human liver microsomes. We also used cDNAexpressed human cytochromes P450 (CYPs) to explore the role of human enzymes in COBI metabolism.
RESULTS
Twenty new and three known metabolites of COBI were identified in mouse urine and feces. These new metabolic pathways of COBI include glycine conjugation, N-acetyl cysteine conjugation, morpholine ring-opening, and thiazole ring-opening. Twelve of COBI metabolites were further confirmed in mouse and human liver microsomes, including nine new metabolites. Consistent with the previous report, CYP3A4 and CYP2D6 were determined as the major enzymes that contribute to COBI metabolism.
CONCLUSION
This study provided a full map of COBI metabolism. These results can be used to manage CYP-mediated drug-drug interactions and adverse drug reactions that are associated with COBI-containing regimens in human.
背景
考比司他（COBI）是一种抗逆转录病毒治疗的药物增强剂。
目的
本研究旨在剖析COBI的代谢途径，并确定参与COBI代谢的酶。
方法
我们在小鼠和人肝微粒体中筛选COBI代谢物。我们还使用cDNA表达的人细胞色素P450（CYPs）来探究人酶在COBI代谢中的作用。
结果
在小鼠尿液和粪便中鉴定出20种新的和3种已知的COBI代谢物。COBI的这些新代谢途径包括甘氨酸结合、N - 乙酰半胱氨酸结合、吗啉环开环和噻唑环开环。12种COBI代谢物在小鼠和人肝微粒体中得到进一步证实，其中包括9种新代谢物。与之前的报告一致，CYP3A4和CYP2D6被确定为参与COBI代谢的主要酶。
结论
本研究提供了COBI代谢的完整图谱。这些结果可用于管理CYP介导的药物 - 药物相互作用以及与含COBI方案相关的人类药物不良反应。
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