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
Language English Country England, Great Britain Media print-electronic
Document type Journal Article
PubMed
29067789
DOI
10.1111/bcpt.12922
Knihovny.cz E-resources
- MeSH
- Alzheimer Disease drug therapy MeSH
- Biological Availability MeSH
- Cholinesterase Inhibitors chemical synthesis metabolism pharmacokinetics therapeutic use MeSH
- Hydrolysis MeSH
- Hydroxylation MeSH
- Microsomes, Liver metabolism MeSH
- Rats MeSH
- Humans MeSH
- Metabolic Networks and Pathways MeSH
- Brain drug effects MeSH
- Pilot Projects MeSH
- Piperazines chemical synthesis metabolism pharmacokinetics therapeutic use MeSH
- Rats, Wistar MeSH
- Tacrine analogs & derivatives chemical synthesis metabolism pharmacokinetics therapeutic use MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- 7-methoxy-N-(2-(4-(3-methylbenzyl)piperazine-1-yl)ethyl)-1,2,3,4-tetrahydroacridin-9-amine MeSH Browser
- Cholinesterase Inhibitors MeSH
- N-(2-(4-(3-bromobenzyl)piperazine-1-yl)ethyl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine MeSH Browser
- Piperazines MeSH
- Tacrine MeSH
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'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 AUCtotal 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.
Biomedical Research Center University Hospital Hradec Kralove Czech Republic
Department of Cellular Biology and Pharmacology Florida International University Miami FL USA
Institute of Clinical Biochemistry and Diagnostic University Hospital Hradec Kralove Czech Republic
References provided by Crossref.org
