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Drug reactive metabolite mass spectrum detection probe and application thereof

A technology for metabolites and drug reactions, applied in the field of detection, can solve the problems of inability to capture hard reactive metabolites, inability to obtain comprehensive information on drug reactive metabolites, narrow capture range of drug reactive metabolites, etc.

Active Publication Date: 2017-05-31
SHANGHAI UNTANGLED BIOSCIENCES CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The biggest defect of the glutathione probe is that the capture range of drug-reactive metabolites is narrow, and hard-reactive metabolites cannot be captured, so comprehensive information on drug-reactive metabolites cannot be obtained

Method used

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  • Drug reactive metabolite mass spectrum detection probe and application thereof
  • Drug reactive metabolite mass spectrum detection probe and application thereof
  • Drug reactive metabolite mass spectrum detection probe and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] WCK (d8-WCK) is mixed with clozapine, HLM (human liver microsomes), catalysts, etc., and used as an in vitro drug metabolism reaction system of human liver microsomes. After LC-MSMS (liquid chromatography-mass spectrometry) detection, Neutral loss map and product ion scan map are obtained by neutral loss scan and product ion scan, respectively as figure 1 and figure 2 shown.

[0057] Clozapine is dehydrogenated during the enzymatic reaction to produce reactive metabolites, which rapidly combine with the sulfhydryl groups in WCK (d8-WCK) to form almost equal adducts with molecular weights of 759 and 767, respectively, such as image 3 shown. Under the neutral loss scan of the electrospray positive ion mode, the neutral group with a molecular weight of 186Da can be lost and detected, and the precursor ions with a molecular weight difference of 8Da appear at the same time, which can better eliminate the interference of impurities in complex biological matrices, such as ...

Embodiment 2

[0060] WCK (d8-WCK) was mixed with thienylfuran and enzyme reaction incubation solution. After LC-MSMS detection, thienylfuran produced two reactive metabolites during the metabolic process. One of them combines with the thiol and amino groups in the oligopeptide probe to form a stable adduct I, and the other combines with a strong nucleophilic amino group to form a stable adduct II due to its strong electrophilicity, such as Figure 4 shown. like Figure 4 The neutral loss diagram and product ion scanning diagram corresponding to adduct Ⅰ are as follows: Figure 5 and Figure 6 shown. like Figure 4 The neutral loss diagram and product ion scanning diagram corresponding to adduct II are as follows: Figure 7 and Figure 8 shown. This shows that the oligopeptide probe WCK can be successfully applied to the capture of hard drug-reactive metabolites in actual samples, and has a good mass spectrometry response.

Embodiment 3

[0062] Similarly, WCK (d8-WCK) was reacted with acetaminophen and mefenamic acid respectively, and after LC-MSMS detection, the neutral loss diagrams of each adduct were respectively obtained, as shown in Figure 9 Shown in A and B. This shows that the oligopeptide probe WCK can be successfully applied to the capture of reactive metabolites in actual samples, and has a good mass spectrometry response.

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Abstract

The invention discloses a drug reactive metabolite mass spectrum detection probe and application thereof. The drug reactive metabolite mass spectrum detection probe is oligopeptide composed of 3-6 common amino acids. The oligopeptide comprises at least one cysteine and at least one lysine. Experimental research shows that the oligopeptide formed by the amino acids is used as the drug reactive metabolite mass spectrum detection probe; the drug reactive metabolite mass spectrum detection probe is capable of capturing hard drug reactive metabolite molecules and is also capable of capturing soft drug reactive metabolite molecules, so that the capturing range of the probe is expanded, and then the comprehensive information of drug reactive metabolite products can be obtained; the probe is particularly applied to structural identification of the drug reactive metabolite molecules, high-throughput screening of drug metabolism in the earlier period of research and development of new drugs, latent evaluation of toxic and side effects of the drugs and research of the occurrence mechanism of toxic and side effects of the drugs.

Description

technical field [0001] The invention relates to the technical field of detection, in particular to a drug reactive metabolite mass spectrum detection probe and its application. Background technique [0002] Drugs are generally converted into highly polar and low-toxic products after metabolism to be excreted from the body, but some drugs will produce a class of intermediates that are prone to chemical reactions during the metabolism process, and these substances are easy to combine with biological macromolecular proteins and nucleic acids. Covalent combination of substances such as liver, which in turn leads to adverse drug reactions such as liver damage and body allergies. For such drug-reactive metabolites with high reactivity, low stability, and low content, stable adducts formed with capture reagents are usually used for mass spectrometry detection. The current literature reports that glutathione and its analogs are used as derivative reagents to capture drug-reactive m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N27/62
CPCG01N27/62
Inventor 郭宾滕浩程雨晴叶美玲魏丽娟
Owner SHANGHAI UNTANGLED BIOSCIENCES CO LTD
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