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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

J. Zdarova Karasova, M. Mzik, M. Hroch, J. Korabecny, E. Nepovimova, V. Vorisek, V. Palicka, K. Kuca,

. 2018 ; 122 (4) : 373-382. [pub] 20171215

Language English Country England, Great Britain

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc19001131

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.

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$a 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 / $c J. Zdarova Karasova, M. Mzik, M. Hroch, J. Korabecny, E. Nepovimova, V. Vorisek, V. Palicka, K. Kuca,
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$a 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.
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$a Mzik, Martin $u Institute of Clinical Biochemistry and Diagnostic, University Hospital, Hradec Kralove, Czech Republic.
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$a Hroch, Milos $u Department of Medical Biochemistry, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic.
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$a Korabecny, Jan $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defense, Hradec Kralove, Brno, Czech Republic. Biomedical Research Center, University Hospital, Hradec Kralove, Czech Republic.
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$a Nepovimova, Eugenie $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defense, Hradec Kralove, Brno, Czech Republic.
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$a Vorisek, Viktor $u Institute of Clinical Biochemistry and Diagnostic, University Hospital, Hradec Kralove, Czech Republic.
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$a Palicka, Vladimir $u Institute of Clinical Biochemistry and Diagnostic, University Hospital, Hradec Kralove, Czech Republic.
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$a Kuca, Kamil $u Biomedical Research Center, University Hospital, Hradec Kralove, Czech Republic. Department of Cellular Biology and Pharmacology, Florida International University, Miami, FL, USA.
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