UHPLC-Orbitrap study of the first phase tacrine in vitro metabolites and related Alzheimer's drug candidates using human liver microsomes

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00179906%3A_____%2F23%3A10459054" target="_blank" >RIV/00179906:_____/23:10459054 - isvavai.cz</a>

Alternative codes found

RIV/60162694:G44__/24:00558723 RIV/00216208:11160/23:10459054

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=6jS3P3rdQ5" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=6jS3P3rdQ5</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.jpba.2022.115154" target="_blank" >10.1016/j.jpba.2022.115154</a>

Result language

angličtina

Original language name

UHPLC-Orbitrap study of the first phase tacrine in vitro metabolites and related Alzheimer's drug candidates using human liver microsomes

Original language description

Tacrine was the first drug used in the therapy of Alzheimer&apos;s disease (AD) and is one of the leading structures frequently pursued in the drug discovery of novel candidates for tackling AD. However, because tacrine has been withdrawn from the market due to its hepatotoxicity, ascribed to specific metabolites, concerns are high about the toxicity profile of newly developed compounds related to tacrine. From the point of view of drug safety, the formation of metabolites must be uncovered and analyzed. Bearing in mind that the main culprit of tacrine hepatotoxicity is its biotransformation to hydroxylated metabolites, human liver microsomes were used as a biotransformation model. Our study aims to clarify phase I metabolites of three potentially non-toxic tacrine derivatives (7-methoxytacrine, 6-chlorotacrine, 7-phenoxytacrine) and to semi-quantitatively determine the relative amount of individual metabolites as potential culprits of tacrine-based hepatotoxicity. For this purpose, a new selective UHPLC-Orbitrap method has been developed. Applying UHPLC-Orbitrap method, two as yet unpublished tacrine and 7-methoxytacrine monohydroxylated metabolites have been found and completely characterized, and the separation of ten dihydroxylated tacrine and 7-methoxytacrine metabolites was achieved for the first time. Moreover, the structures of several new metabolites of 7-phenoxytacrine and 6-chlorotacrine have been identified. In addition, the relative amount of these newly observed metabolites was determined. Based on the results and known facts about the toxicity of tacrine metabolites published so far, it appears that 7-phenoxytacrine and 6-chlorotacrine could be substantially less hepatotoxic compared to tacrine, and could potentially pave the way for metabolically safe molecules applicable in AD therapy.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10406 - Analytical chemistry

Project

<a href="/en/project/NU20-08-00296" target="_blank" >NU20-08-00296: Dually acting cognitive enhancers for palliative treatment of Alzheimer´s disease</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2023

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Journal of Pharmaceutical and Biomedical Analysis

ISSN

0731-7085

e-ISSN

1873-264X

Volume of the periodical

224

Issue of the periodical within the volume

FEB

Country of publishing house

GB - UNITED KINGDOM

Number of pages

12

Pages from-to

115154

UT code for WoS article

000891784600006

EID of the result in the Scopus database

2-s2.0-85142758366