LAUSR

Abstract This year’s review on bioactivation and reactivity began as a part of the annual review on biotransformation and bioactivation led by Cyrus Khojasteh (see references). Increased contributions from experts in the field led to the development of a stand alone edition for the first time this year focused specifically on bioactivation and reactivity. Our objective for this review is to highlight and share articles which we deem influential and significant regarding the development of covalent inhibitors, mechanisms of reactive metabolite formation, enzyme inactivation, and drug safety. Based on the selected articles, we created two sections: (1) reactivity and enzyme inactivation, and (2) bioactivation mechanisms and safety (Table 1). Several biotransformation experts have contributed to this effort from academic and industry settings. Table 1. Articles covered in this review. Title First author Source Reactivity & enzyme inactivation 1 The inactivation of human aldehyde oxidase 1 by hydrogen peroxide and superoxide. C Garrido Drug Metab Dispos 49:729–735, 2021 2 Icotinib induces mechanism-based inactivation of recombinant human CYP3A4/5 possibly via heme destruction by ketene intermediate. C Sun Drug Metab Dispos 49:892–901, 2021 3 Evobrutinib, a covalent Bruton’s tyrosine kinase inhibitor: Mass balance, elimination route, and metabolism in healthy participants. H Scheible Clin Transl Sci 14: 2420–2430, 2021 Bioactivation mechanisms & safety 4 Metabolic activation of atomoxetine mediated by cytochrome P450 2D6. Y You Chem Res Toxicol 34:2135–2144, 2021 5 Mechanism-based insights into removing the mutagenicity of aromatic amines by small structural alterations. I Shamovsky J Med Chem 64: 8545–8563, 2021 6 Investigating the mechanism of trimethoprim-induced skin rash and liver injury. Y Cao J Toxicol Sci 180:17–25, 2021 7 Bioactivation of clozapine by mitochondria of the murine heart: Possible cause of cardiotoxicity. E Arzuk Toxicology 447: 152628, 2021 8 CYP2C9 and 3A4 play opposing roles in bioactivation and detoxification of diphenylamine NSAIDs. Mary Alexandra Schleiff Biochem Pharmacol 194:114824, 2021 9 Metabolic activation and cytotoxicity of labetalol hydrochloride mediated by sulfotransferases. L Yang Chem Res Toxicol 34:1612–1618, 2021 10 Cytochrome P450 binding and bioactivation of tumor-targeted duocarmycin agents. AG Bart Drug Metab Dispos 50:49–57, 2022 11 Preclinical metabolism and disposition of an orally bioavailable macrocyclic FXIa inhibitor. SA Chacko Xenobiotica 51:933–948, 2021 12 Identification of an isoform catalyzing the CoA conjugation of nonsteroidal anti-inflammatory drugs and the evaluation of the expression levels of acyl-CoA synthetases in the human liver. H Hashizume Biochem Pharmacol 183:114303, 2021 13 Identification and characterization of in vitro, in vivo, and reactive metabolites of tandutinib using liquid chromatography ion trap mass spectrometry. NS Al-Shakliah Anal Methods 13: 399–410, 2021 14 Idiosyncratic drug-induced liver injury: Mechanistic and clinical challenges. A Jee Int J Mol Sci 22: 2954, 2021