The New Acetylcholinesterase Inhibitors PC-37 and PC-48 (7-Methoxytacrine-Donepezil-Like Compounds): Characterization of Their Metabolites in Human Liver Microsomes, Pharmacokinetics and In Vivo Formation of the Major Metabolites in Rats

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11150%2F18%3A10373992" target="_blank" >RIV/00216208:11150/18:10373992 - isvavai.cz</a>

Alternative codes found

RIV/60162694:G44__/18:43889470 RIV/00179906:_____/18:10373992

Result on the web

<a href="https://onlinelibrary.wiley.com/doi/abs/10.1111/bcpt.12922" target="_blank" >https://onlinelibrary.wiley.com/doi/abs/10.1111/bcpt.12922</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1111/bcpt.12922" target="_blank" >10.1111/bcpt.12922</a>

Result language

angličtina

Original language name

The New Acetylcholinesterase Inhibitors PC-37 and PC-48 (7-Methoxytacrine-Donepezil-Like Compounds): Characterization of Their Metabolites in Human Liver Microsomes, Pharmacokinetics and In Vivo Formation of the Major Metabolites in Rats

Original language description

The objective of this study was to elucidate the pharmacokinetics and metabolite formation of newly developed non-selective AChE/BChE 7-MEOTA-donepezil-like inhibitors for potential therapeutic use in Alzheimer&apos;s disease (AD) patients. The chemical structures of metabolites were defined during incubation with human liver microsomes, and subsequently, the metabolization was verified in in vivo study. In vitro metabolic profiling revealed the formation of nine major metabolites in the case of PC-37 and eight metabolites of PC-48. Hydroxylation and the enzymatic hydrolysis of bonds close to the piperazine ring appeared to be the principal metabolic pathways in vitro. Of these metabolites, M1-M7 of PC-37 and M1-M6 of PC-48 were confirmed under in vivo conditions. Pilot pharmacokinetic experiments in rats were focused on the absorption, distribution and elimination of these compounds. Absorption after i.m. application was relatively fast; the bioavailability expressed as AUC(total) was 28179 +/- 4691 min.ng/mL for PC-37 and 23374 +/- 4045 min.ng/mL for PC-48. Both compounds showed ability to target the central nervous system, with brain concentrations exceeding those in plasma. The maximal brain concentrations are approximately two times higher than the plasma concentrations. The relatively high brain concentrations persisted throughout the experiment until 24 hr after application. Elimination via the kidneys (urine) significantly exceeded elimination via the liver (bile). All these characteristics are crucial for new candidates intended for AD treatment. The principle metabolic pathways that were verified in the in vivo study do not show any evidence for formation of extremely toxic metabolites, but this needs to be confirmed by further studies.

Czech name

—

Czech description

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Type

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

CEP classification

—

OECD FORD branch

30104 - Pharmacology and pharmacy

Project

<a href="/en/project/NV15-30954A" target="_blank" >NV15-30954A: Development of multi-target drugs for Alzheimer´s disease: combination of AChE inhibitor and melatonin derivative</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2018

Confidentiality

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

Name of the periodical

Basic &amp; Clinical Pharmacology &amp; Toxicology

ISSN

1742-7835

e-ISSN

—

Volume of the periodical

122

Issue of the periodical within the volume

4

Country of publishing house

GB - UNITED KINGDOM

Number of pages

10

Pages from-to

373-382

UT code for WoS article

000427113100002

EID of the result in the Scopus database

2-s2.0-85041214635