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The release of aromatic amines from drugs and other xenobiotics resulting from the hydrolysis of metabolically labile amide bonds presents a safety risk through several mechanisms, including geno-, hepato- and nephrotoxicity. Whilst multiple  in vitro  systems used for studying metabolic stability display serine hydrolase activity, responsible for the hydrolysis of amide bonds, they vary in their efficiency and selectivity. Using a range of amide-containing probe compounds (0.5–10 µM), we have investigated the hydrolytic activity of several rat, minipig and human-derived  in vitro  systems - including Supersomes, microsomes, S9 fractions and hepatocytes - with respect to their previously observed human  in vivo  metabolism. In our hands, human carboxylesterase Supersomes and rat S9 fractions systems showed relatively poor prediction of human  in vivo  metabolism. Rat S9 fractions, which are commonly utilised in the Ames test to assess mutagenicity, may be limited in the detection of genotoxic metabolites from aromatic amides due to their poor concordance with human  in vivo  amide hydrolysis. In this study, human liver microsomes and minipig subcellular fractions provided more representative models of human  in vivo  hydrolytic metabolism of the aromatic amide compounds tested.

Metabolic Hydrolysis of Aromatic Amides in Selected Rat, Minipig, and Human In Vitro Systems