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CRV431（一种用于慢性乙型肝炎的新型口服候选药物）的体外I期代谢

In Vitro Phase I Metabolism of CRV431, a Novel Oral Drug Candidate for Chronic Hepatitis B.

作者信息

Trepanier Daniel J, Ure Daren R, Foster Robert T

机构信息

ContraVir Pharmaceuticals Inc., Edison, NJ 08837, USA.

出版信息

Pharmaceutics. 2017 Nov 9;9(4):51. doi: 10.3390/pharmaceutics9040051.

DOI:10.3390/pharmaceutics9040051
PMID:29120380
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5750657/
Abstract

The cytochrome P450-mediated Phase I in vitro metabolism of CRV431 was studied using selective chemical inhibition and recombinant human enzymes. Additionally, the metabolic profile of CRV431 in human, rat, and monkey liver microsomes was investigated. Liver microsomes were incubated for 0-80 min with CRV431, and the metabolite profile was assessed by electrospray ionization liquid chromatography mass spectrometry (ESI-LCMS). CRV431 was extensively metabolized through oxidation to produce various hydroxylated and demethylated species. Species identified included monohydroxylated CRV431 (two distinct products), dihydroxylated CRV431, demethylated CRV431 (two distinct products), demethylated and hydroxylated CRV431 (two distinct products), didemethylated and hydroxylated CRV431, and didemethylated and dihydroxylated CRV431. The magnitude of metabolism was greatest in monkey, followed by human, followed by rat. Importantly, all of the species identified in human microsomes were correspondingly identified in monkey and/or rat microsomes. Human liver microsome studies using selective chemical inhibition, as well as studies using recombinant human cytochrome P450 enzymes, revealed that the major enzymes involved are cytochromes P450 3A4 and 3A5. Enzymes 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6 are not involved in the in vitro metabolism of CRV431. This information will be useful for the further development of CRV431 both preclinically and clinically.

摘要

使用选择性化学抑制和重组人酶研究了CRV431的细胞色素P450介导的I相体外代谢。此外，还研究了CRV431在人、大鼠和猴肝微粒体中的代谢概况。将肝微粒体与CRV431孵育0 - 80分钟，通过电喷雾电离液相色谱质谱法（ESI-LCMS）评估代谢物概况。CRV431通过氧化广泛代谢，产生各种羟基化和去甲基化产物。鉴定出的产物包括单羟基化CRV431（两种不同产物）、二羟基化CRV431、去甲基化CRV431（两种不同产物）、去甲基化和羟基化CRV431（两种不同产物）、双去甲基化和羟基化CRV431以及双去甲基化和二羟基化CRV431。代谢程度在猴中最大，其次是人，然后是大鼠。重要的是，在人微粒体中鉴定出的所有产物在猴和/或大鼠微粒体中也相应被鉴定出。使用选择性化学抑制的人肝微粒体研究以及使用重组人细胞色素P450酶的研究表明，主要参与的酶是细胞色素P450 3A4和3A5。酶1A2、2B6、2C8、2C9、2C19和2D6不参与CRV431的体外代谢。这些信息将有助于CRV431在临床前和临床的进一步开发。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03cc/5750657/4304890b2c49/pharmaceutics-09-00051-g011.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03cc/5750657/22c9c598ff79/pharmaceutics-09-00051-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03cc/5750657/67d786323df5/pharmaceutics-09-00051-g009a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03cc/5750657/3646edf5a336/pharmaceutics-09-00051-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03cc/5750657/4304890b2c49/pharmaceutics-09-00051-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03cc/5750657/d72766622293/pharmaceutics-09-00051-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03cc/5750657/d632f81df481/pharmaceutics-09-00051-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03cc/5750657/513eb43a5fc1/pharmaceutics-09-00051-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03cc/5750657/b205ce76323c/pharmaceutics-09-00051-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03cc/5750657/ecc1fbaed358/pharmaceutics-09-00051-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03cc/5750657/80af01baafca/pharmaceutics-09-00051-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03cc/5750657/76c8ae217d41/pharmaceutics-09-00051-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03cc/5750657/22c9c598ff79/pharmaceutics-09-00051-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03cc/5750657/67d786323df5/pharmaceutics-09-00051-g009a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03cc/5750657/3646edf5a336/pharmaceutics-09-00051-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03cc/5750657/4304890b2c49/pharmaceutics-09-00051-g011.jpg

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