ADMET parameters of tacrine and its metabolites confirm unsuitability of Sus scrofa f. domestica model to study tacrine-associated hepatotoxicity
Jazyk angličtina Země Irsko Médium print-electronic
Typ dokumentu časopisecké články
PubMed
40319996
DOI
10.1016/j.cbi.2025.111548
PII: S0009-2797(25)00178-4
Knihovny.cz E-zdroje
- Klíčová slova
- Biotransformation, Distribution, Hepatotoxicity, Pig model, Tacrine,
- MeSH
- biotransformace MeSH
- cholinesterasové inhibitory toxicita farmakokinetika MeSH
- játra * účinky léků metabolismus patologie MeSH
- lékové postižení jater * metabolismus patologie MeSH
- lidé MeSH
- prasata MeSH
- Sus scrofa MeSH
- takrin * farmakokinetika toxicita metabolismus analogy a deriváty MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- cholinesterasové inhibitory MeSH
- takrin * MeSH
Tacrine, the first approved drug against Alzheimer's disease (AD), was withdrawn from clinical use due to serious adverse effects.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.
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