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UHPLC-Orbitrap study of the first phase tacrine in vitro metabolites and related Alzheimer's drug candidates using human liver microsomes

M. Novak, B. Svobodova, J. Konecny, A. Kuratkova, L. Nevosadova, L. Prchal, J. Korabecny, VM. Lauschke, O. Soukup, R. Kučera

. 2023 ; 224 (-) : 115154. [pub] 20221112

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc23004248

Tacrine was the first drug used in the therapy of Alzheimer's disease (AD) and is one of the leading structures frequently pursued in the drug discovery of novel candidates for tackling AD. However, because tacrine has been withdrawn from the market due to its hepatotoxicity, ascribed to specific metabolites, concerns are high about the toxicity profile of newly developed compounds related to tacrine. From the point of view of drug safety, the formation of metabolites must be uncovered and analyzed. Bearing in mind that the main culprit of tacrine hepatotoxicity is its biotransformation to hydroxylated metabolites, human liver microsomes were used as a biotransformation model. Our study aims to clarify phase I metabolites of three potentially non-toxic tacrine derivatives (7-methoxytacrine, 6-chlorotacrine, 7-phenoxytacrine) and to semi-quantitatively determine the relative amount of individual metabolites as potential culprits of tacrine-based hepatotoxicity. For this purpose, a new selective UHPLC-Orbitrap method has been developed. Applying UHPLC-Orbitrap method, two as yet unpublished tacrine and 7-methoxytacrine monohydroxylated metabolites have been found and completely characterized, and the separation of ten dihydroxylated tacrine and 7-methoxytacrine metabolites was achieved for the first time. Moreover, the structures of several new metabolites of 7-phenoxytacrine and 6-chlorotacrine have been identified. In addition, the relative amount of these newly observed metabolites was determined. Based on the results and known facts about the toxicity of tacrine metabolites published so far, it appears that 7-phenoxytacrine and 6-chlorotacrine could be substantially less hepatotoxic compared to tacrine, and could potentially pave the way for metabolically safe molecules applicable in AD therapy.

Citace poskytuje Crossref.org

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$a Novak, M $u Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 50005 Hradec Kralove, Czech Republic. Electronic address: martin.novak@fnhk.cz
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$a Tacrine was the first drug used in the therapy of Alzheimer's disease (AD) and is one of the leading structures frequently pursued in the drug discovery of novel candidates for tackling AD. However, because tacrine has been withdrawn from the market due to its hepatotoxicity, ascribed to specific metabolites, concerns are high about the toxicity profile of newly developed compounds related to tacrine. From the point of view of drug safety, the formation of metabolites must be uncovered and analyzed. Bearing in mind that the main culprit of tacrine hepatotoxicity is its biotransformation to hydroxylated metabolites, human liver microsomes were used as a biotransformation model. Our study aims to clarify phase I metabolites of three potentially non-toxic tacrine derivatives (7-methoxytacrine, 6-chlorotacrine, 7-phenoxytacrine) and to semi-quantitatively determine the relative amount of individual metabolites as potential culprits of tacrine-based hepatotoxicity. For this purpose, a new selective UHPLC-Orbitrap method has been developed. Applying UHPLC-Orbitrap method, two as yet unpublished tacrine and 7-methoxytacrine monohydroxylated metabolites have been found and completely characterized, and the separation of ten dihydroxylated tacrine and 7-methoxytacrine metabolites was achieved for the first time. Moreover, the structures of several new metabolites of 7-phenoxytacrine and 6-chlorotacrine have been identified. In addition, the relative amount of these newly observed metabolites was determined. Based on the results and known facts about the toxicity of tacrine metabolites published so far, it appears that 7-phenoxytacrine and 6-chlorotacrine could be substantially less hepatotoxic compared to tacrine, and could potentially pave the way for metabolically safe molecules applicable in AD therapy.
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$a Konecny, J $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 50005 Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Trebesska 1575, 50005 Hradec Kralove, Czech Republic. Electronic address: jan.konecny@fnhk.cz
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$a Kuratkova, A $u Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic. Electronic address: kuratkoa@faf.cuni.cz
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$a Nevosadova, L $u Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic. Electronic address: nevosadl@faf.cuni.cz
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$a Prchal, L $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 50005 Hradec Kralove, Czech Republic. Electronic address: lukas.prchal@fnhk.cz
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$a Korabecny, J $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 50005 Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Trebesska 1575, 50005 Hradec Kralove, Czech Republic. Electronic address: jan.korabecny@fnhk.cz
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$a Lauschke, V M $u Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden; Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany; University of Tübingen, 72074 Tübingen, Germany. Electronic address: Volker.lauschke@ki.se
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$a Soukup, O $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 50005 Hradec Kralove, Czech Republic. Electronic address: ondrej.soukup@fnhk.cz
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$a Kučera, R $u Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic. Electronic address: kucerar@faf.cuni.cz
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