Tacrine First-Phase Biotransformation and Associated Hepatotoxicity: A Possible Way to Avoid Quinone Methide Formation

• DOI: 10.1021/acschembio.3c00219
• Publication Date: 2023-08-25T10:57:16Z
• Authors: Martin Novak; Marie Vajrychova; Stefania Koutsilieri; Despoina-Christin...; Tereza Kobrlova; Lukas Prchal; Barbora Svobodova; Jan Korabecny; Tomas Zarybnicky; Lucie Raisova-Stu...; Lenka Skalova; Volker M. Lauschke; Radim Kučera; Ondrej Soukup
• Keywords: Tacrine; Biotransformation

Tacrine was withdrawn from clinical use as a drug against Alzheimer's disease in 2013, mainly due to drug-induced liver injury. The culprit of tacrine-associated hepatotoxicity is believed be the 7-OH-tacrine metabolite, possible precursor quinone methide (Qmeth), which binds intracellular -SH proteins. In our study, several different animal and human models (liver microsomes, primary hepatocytes, slices) were used investigate biotransformation tacrine its 7-substituted analogues (7-methoxy-, 7-phenoxy-, 7-OH-tacrine). Our goal find most appropriate vitro model for studying and, through rational structure modifications, develop derivatives that are less prone Qmeth formation. results show none tested accurately mimic biotransformation; however, murine seems more suitable than rat model. metabolism overall mimicked three-dimensional (3D) spheroid cultures hepatocytes (PHHs). this system, 7-methoxytacrine hydroxylated 7-OH-tacrine, whereas 7-phenoxytacrine formed, expected, only trace amounts. Surprisingly, study showed least hepatotoxic (7-OH-tacrine < 7-phenoxytacrine) even after doses had been adjusted achieve same concentrations. formation Qmeth-cysteine Qmeth-glutathione adducts microsome incubation confirmed by all studied derivatives, but these findings not with 3D PHH spheroids. Therefore, presented data call into question suggested previously hypothesized mechanism toxicity, open new avenues chemical modifications improve safety novel derivatives.