ADMET parameters of tacrine and its metabolites confirm unsuitability of Sus scrofa f. domestica model to study tacrine-associated hepatotoxicity

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00179906%3A_____%2F25%3A10498805" target="_blank" >RIV/00179906:_____/25:10498805 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/60162694:G44__/26:00566017

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=_EFWOi7~-E" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=_EFWOi7~-E</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.cbi.2025.111548" target="_blank" >10.1016/j.cbi.2025.111548</a>

Jazyk výsledku

angličtina

Název v původním jazyce

ADMET parameters of tacrine and its metabolites confirm unsuitability of Sus scrofa f. domestica model to study tacrine-associated hepatotoxicity

Popis výsledku v původním jazyce

Tacrine, the first approved drug against Alzheimer&apos;s disease (AD), was withdrawn from clinical use due to serious adverse effects. The main concern was the human hepatotoxicity, stemming probably from the liver biotransformation and clinically manifested as hepatocellular necrosis, and lobular hepatitis. Concerning the biotransformation, 7-OH-tacrine metabolite is generally suspected of being a precursor of toxic quinone methide, which binds to intracellular -SH proteins and/or depletes intracellular glutathione, and by that probably causes the hepatotoxicity. However, to study these toxic effects, proper animal model is needed to monitor the interspecies differences of metabolism. To fully describe in vivo ADMET parameters of tacrine, five experimental pigs (Sus scrofa f. domestica), as the most physiologically human-like in vivo model showing similar tacrine biotransformation, were used. We studied tacrine and its metabolites ADMET characteristics after both acute i.g. single dose and chronic 42 days p.o daily dose administration of 200 mg of tacrine. Tacrine and its two major metabolites show Tmax in plasma of 360 min, so the absorption is much slower than in human (Tmax =120 min) and are primarily distributed to the gastro-intestinal tract and CNS. Furthermore, due to the lower activity of CYP1A2 in pigs, tacrine is biotransformed much less efficiently than in humans. This study showed that tacrine accumulates only in adipose tissue, and organ histology and plasma biochemistry assessment revealed no signs of hepatotoxicity even after chronic tacrine administration. Pigs are therefore an unsuitable human-like animal model for evaluating tacrine toxicity.

Název v anglickém jazyce

ADMET parameters of tacrine and its metabolites confirm unsuitability of Sus scrofa f. domestica model to study tacrine-associated hepatotoxicity

Popis výsledku anglicky

Tacrine, the first approved drug against Alzheimer&apos;s disease (AD), was withdrawn from clinical use due to serious adverse effects. The main concern was the human hepatotoxicity, stemming probably from the liver biotransformation and clinically manifested as hepatocellular necrosis, and lobular hepatitis. Concerning the biotransformation, 7-OH-tacrine metabolite is generally suspected of being a precursor of toxic quinone methide, which binds to intracellular -SH proteins and/or depletes intracellular glutathione, and by that probably causes the hepatotoxicity. However, to study these toxic effects, proper animal model is needed to monitor the interspecies differences of metabolism. To fully describe in vivo ADMET parameters of tacrine, five experimental pigs (Sus scrofa f. domestica), as the most physiologically human-like in vivo model showing similar tacrine biotransformation, were used. We studied tacrine and its metabolites ADMET characteristics after both acute i.g. single dose and chronic 42 days p.o daily dose administration of 200 mg of tacrine. Tacrine and its two major metabolites show Tmax in plasma of 360 min, so the absorption is much slower than in human (Tmax =120 min) and are primarily distributed to the gastro-intestinal tract and CNS. Furthermore, due to the lower activity of CYP1A2 in pigs, tacrine is biotransformed much less efficiently than in humans. This study showed that tacrine accumulates only in adipose tissue, and organ histology and plasma biochemistry assessment revealed no signs of hepatotoxicity even after chronic tacrine administration. Pigs are therefore an unsuitable human-like animal model for evaluating tacrine toxicity.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/GA23-07570S" target="_blank" >GA23-07570S: Biotransformace takrinu implikující jeho hepatotoxicitu</a><br>

Návaznosti

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

Rok uplatnění

2025

Kód důvěrnosti údajů

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

Název periodika

Chemico-Biological Interactions

ISSN

0009-2797

e-ISSN

1872-7786

Svazek periodika

416

Číslo periodika v rámci svazku

AUG

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

7

Strana od-do

111548

Kód UT WoS článku

001489932400002

EID výsledku v databázi Scopus

2-s2.0-105004313650