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Since 2004, synthetic cannabinoids have been used recreationally, although several of the compounds have been shown to cause severe toxicity in humans. In this study, the metabolism of two indazole carboxamide derivatives, AB\u2010PINACA and AB\u2010FUBINACA, was investigated by using human liver microsomes (HLM). For both compounds, a major metabolic pathway was the enzymatic hydrolysis of the primary amide, resulting in the major metabolites AB\u2010PINACA\u2010COOH and AB\u2010FUBINACA\u2010COOH. Other major metabolic pathways were mono\u2010hydroxylation of the N\u2010pentyl chain in AB\u2010PINACA and mono\u2010hydroxylation of the 1\u2010amino\u20103\u2010methyl\u20101\u2010oxobutane moiety in AB\u2010FUBINACA. To identify the enzyme(s) responsible for the amide hydrolysis, incubations with recombinant carboxylesterases and human serum, as well as inhibition studies in HLM and human pulmonary microsomes (HPM) were performed. Carboxylesterase 1 (CES1) was identified as the major human hepatic and pulmonary enzyme responsible for the amide hydrolysis.We employed similar studies to identify the esterase(s) involved in the previously described hydrolytic metabolism of two quinolineindole synthetic cannabinoids, PB\u201022 and 5F\u2010PB\u201022, as well as the closely related compound, BB\u201022. Our investigations again revealed CES1 to be the key enzyme catalyzing these reactions. The identified major metabolites of AB\u2010PINACA and AB\u2010FUBINACA are likely to be useful in documenting drug usage in forensic and clinical screening. Additionally, the identification of CES1 as the main enzyme hydrolyzing these compounds improves our knowledge in the emerging field of xenobiotic metabolism by esterases. 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