{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T01:37:48Z","timestamp":1789781868608,"version":"4.0.1"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,2,5]],"date-time":"2018-02-05T00:00:00Z","timestamp":1517788800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,2,5]],"date-time":"2018-02-05T00:00:00Z","timestamp":1517788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    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\n                    <jats:italic>in vitro<\/jats:italic>\n                    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\u201310\u2009\u00b5M), we have investigated the hydrolytic activity of several rat, minipig and human-derived\n                    <jats:italic>in vitro<\/jats:italic>\n                    systems - including Supersomes, microsomes, S9 fractions and hepatocytes - with respect to their previously observed human\n                    <jats:italic>in vivo<\/jats:italic>\n                    metabolism. In our hands, human carboxylesterase Supersomes and rat S9 fractions systems showed relatively poor prediction of human\n                    <jats:italic>in vivo<\/jats:italic>\n                    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\n                    <jats:italic>in vivo<\/jats:italic>\n                    amide hydrolysis. In this study, human liver microsomes and minipig subcellular fractions provided more representative models of human\n                    <jats:italic>in vivo<\/jats:italic>\n                    hydrolytic metabolism of the aromatic amide compounds tested.\n                  <\/jats:p>","DOI":"10.1038\/s41598-018-20464-4","type":"journal-article","created":{"date-parts":[[2018,1,30]],"date-time":"2018-01-30T09:39:14Z","timestamp":1517305154000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Metabolic Hydrolysis of Aromatic Amides in Selected Rat, Minipig, and Human In Vitro Systems"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8810-5648","authenticated-orcid":false,"given":"Peter R.","family":"Bradshaw","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8558-7394","authenticated-orcid":false,"given":"Ian D.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel Upcott","family":"Gill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip J.","family":"Butler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clive","family":"Dilworth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5732-9574","authenticated-orcid":false,"given":"Toby J.","family":"Athersuch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,2,5]]},"reference":[{"key":"20464_CR1","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1093\/carcin\/bgp267","volume":"31","author":"PL Skipper","year":"2010","unstructured":"Skipper, P. L. et al. Monocyclic aromatic amines as potential human carcinogens: old is new again. Carcinogenesis 31, 50\u201358 (2010).","journal-title":"Carcinogenesis"},{"key":"20464_CR2","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1023\/A:1025560513308","volume":"252","author":"Y Aizawa","year":"2003","unstructured":"Aizawa, Y. et al. Flutamide-induced hepatic dysfunction in relation to steady-state plasma concentrations of flutamide and its metabolites. Mol Cell Biochem. 252, 149\u2013156 (2003).","journal-title":"Mol Cell Biochem."},{"key":"20464_CR3","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.1124\/dmd.113.051714","volume":"41","author":"R Higuchi","year":"2013","unstructured":"Higuchi, R., Fukami, T., Nakajima, M. & Yokoi, T. Prilocaine- and lidocaine-induced methemoglobinemia is caused by human carboxylesterase-, cyp2e1-, and cyp3a4-mediated metabolic activations. Drug Metab Dispos. 41, 1220\u20131230 (2013).","journal-title":"Drug Metab Dispos."},{"key":"20464_CR4","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1021\/tx00022a001","volume":"4","author":"FP Guengerich","year":"1991","unstructured":"Guengerich, F. P. & Shimada, T. Oxidation of toxic and carcinogenic chemicals by human cytochrome p-450 enzymes. Chem Res Toxicol. 4, 391\u2013407 (1991).","journal-title":"Chem Res Toxicol."},{"key":"20464_CR5","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1007\/BF00615229","volume":"34","author":"M Schulz","year":"1988","unstructured":"Schulz, M., Schmoldt, A., Donn, F. & Becker, H. The pharmacokinetics of flutamide and its major metabolites after a single oral dose and during chronic treatment. Eur J Clin Pharmacol. 34, 633\u2013636 (1988).","journal-title":"Eur J Clin Pharmacol."},{"key":"20464_CR6","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.3109\/00498259309059435","volume":"23","author":"D McKillop","year":"1993","unstructured":"McKillop, D. et al. Metabolism and enantioselective pharmacokinetics of casodex in man. Xenobiotica. 23, 1241\u20131253 (1993).","journal-title":"Xenobiotica."},{"key":"20464_CR7","doi-asserted-by":"publisher","first-page":"266","DOI":"10.12659\/AJCR.890679","volume":"15","author":"S Hussain","year":"2014","unstructured":"Hussain, S. et al. Bicalutamide-induced hepatotoxicity: a rare adverse effect. Am J Case Rep. 15, 266\u2013270 (2014).","journal-title":"Am J Case Rep."},{"key":"20464_CR8","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1016\/S0731-7085(96)01950-4","volume":"15","author":"AW Nicholls","year":"1997","unstructured":"Nicholls, A. W. et al. NMR and HPLC-NMR spectroscopic studies of futile deacetylation in paracetamol metabolites in rat and man. J Pharma Biomed Anal. 15, 901\u2013910 (1997).","journal-title":"J Pharma Biomed Anal."},{"key":"20464_CR9","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1039\/ap9842100013","volume":"21","author":"JD Baty","year":"1984","unstructured":"Baty, J. D., Willis, R. G. & Koh, Y. K. Studies on de-acetylation - re-acetylation reactions using stable isotopes. Anal Proc. 21, 14\u201316 (1984).","journal-title":"Anal Proc."},{"key":"20464_CR10","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1002\/bms.1200160133","volume":"16","author":"JD Baty","year":"1988","unstructured":"Baty, J. D., Lindsay, R. M., Fox, W. R. & Willis, R. G. Stable isotopes as probes for the metabolism of acetanilide in man and the rat. Biomed Environ Mass Spectrom. 16, 183\u2013189 (1988).","journal-title":"Biomed Environ Mass Spectrom."},{"key":"20464_CR11","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/S0022-3565(25)29125-X","volume":"180","author":"JB Keenaghan","year":"1972","unstructured":"Keenaghan, J. B. & Boyes, R. N. The tissue distribution, metabolism and excretion of lidocaine in rats, guinea pigs, dogs and man. J Pharmacol Exp Ther. 180, 454\u2013463 (1972).","journal-title":"J Pharmacol Exp Ther."},{"key":"20464_CR12","doi-asserted-by":"publisher","first-page":"2825","DOI":"10.1016\/0006-2952(72)90206-7","volume":"21","author":"M Hjelm","year":"1972","unstructured":"Hjelm, M., Ragnarsson, B. & Wistrand, P. Biochemical effects of aromatic compounds. III. ferrihaemoglobinaemia and the presence of p-hydroxy-o-toluidine in human blood after the administration of prilocaine. Biochem Pharmacol. 21, 2825\u20132834 (1972).","journal-title":"Biochem Pharmacol."},{"key":"20464_CR13","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/1472-6904-9-3","volume":"9","author":"DM Roberts","year":"2009","unstructured":"Roberts, D. M. et al. Clinical outcomes and kinetics of propanil following acute self-poisoning: a prospective case series. BMC Clin Pharmacol. 9, 3 (2009).","journal-title":"BMC Clin Pharmacol."},{"key":"20464_CR14","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1136\/ewjm.175.3.193","volume":"175","author":"HU Rehman","year":"2001","unstructured":"Rehman, H. U. Methemoglobinemia. West J Med. 175, 193\u2013196 (2001).","journal-title":"West J Med."},{"key":"20464_CR15","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/0163-7258(82)90064-X","volume":"19","author":"P Andrews","year":"1982","unstructured":"Andrews, P., Thyssen, J. & Lorke, D. The biology and toxicology of molluscicides, bayluscide. Pharmacol Ther. 19, 245\u2013295 (1982).","journal-title":"Pharmacol Ther."},{"key":"20464_CR16","doi-asserted-by":"publisher","first-page":"466","DOI":"10.2133\/dmpk.DMPK-12-RV-042","volume":"27","author":"T Fukami","year":"2012","unstructured":"Fukami, T. & Yokoi, T. The emerging role of human esterases. Drug Metab Pharmacokinet. 27, 466\u2013477 (2012).","journal-title":"Drug Metab Pharmacokinet."},{"key":"20464_CR17","doi-asserted-by":"publisher","first-page":"31131","DOI":"10.1074\/jbc.M313666200","volume":"279","author":"C Frick","year":"2004","unstructured":"Frick, C., Atanasov, A. G., Arnold, P., Ozols, J. & Odermatt, A. Appropriate function of 11\u03b2-hydroxysteroid dehydrogenase type 1 in the endoplasmic reticulum lumen is dependent on its n-terminal region sharing similar topological determinants with 50-kda esterase. J Biol Chem. 279, 31131\u201331138 (2004).","journal-title":"J Biol Chem."},{"key":"20464_CR18","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1124\/dmd.111.043067","volume":"40","author":"Y Kobayashi","year":"2012","unstructured":"Kobayashi, Y. et al. Species differences in tissue distribution and enzyme activities of arylacetamide deacetylase in human, rat, and mouse. Drug Metab Dispos. 40, 671\u2013679 (2012).","journal-title":"Drug Metab Dispos."},{"key":"20464_CR19","doi-asserted-by":"publisher","first-page":"483","DOI":"10.3109\/00498254.2015.1089452","volume":"46","author":"R Jones","year":"2016","unstructured":"Jones, R. et al. Shedding light on minipig drug metabolism \u2013 elevated amide hydrolysis in vitro. Xenobiotica. 46, 483\u2013494 (2016).","journal-title":"Xenobiotica."},{"key":"20464_CR20","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/S0041-008X(03)00128-5","volume":"189","author":"EF Brandon","year":"2003","unstructured":"Brandon, E. F., Raap, C. D., Meijerman, I., Beijnen, J. H. & Schellens, J. H. An update on in vitro test methods in human hepatic drug biotransformation research: pros and cons. Toxicol Appl Pharmacol. 189, 233\u2013246 (2003).","journal-title":"Toxicol Appl Pharmacol."},{"key":"20464_CR21","doi-asserted-by":"publisher","first-page":"822","DOI":"10.2174\/138920007782798207","volume":"8","author":"L Jia","year":"2007","unstructured":"Jia, L. & Liu, X. The conduct of drug metabolism studies considered good practice (II): in vitro experiments. Curr Drug Metab. 8, 822\u2013829 (2007).","journal-title":"Curr Drug Metab."},{"key":"20464_CR22","doi-asserted-by":"publisher","first-page":"2281","DOI":"10.1073\/pnas.70.8.2281","volume":"70","author":"BN Ames","year":"1973","unstructured":"Ames, B. N., Durston, W. E., Yamasaki, E. & Lee, F. D. Carcinogens are mutagens: a simple test system combining liver homogenates for activation and bacteria for detection. Proc Natl Acad Sci USA 70, 2281\u20132285 (1973).","journal-title":"Proc Natl Acad Sci USA"},{"key":"20464_CR23","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.mrgentox.2006.10.004","volume":"627","author":"WW Ku","year":"2007","unstructured":"Ku, W. W. et al. Strategy for genotoxicity testing - Metabolic Considerations. Mutat Res. 627, 59\u201377 (2007).","journal-title":"Mutat Res."},{"key":"20464_CR24","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1124\/dmd.112.044537","volume":"40","author":"Y Kobayashi","year":"2012","unstructured":"Kobayashi, Y., Fukami, T., Shimizu, M., Nakajima, M. & Yokoi, T. Contributions of arylacetamide deacetylase and carboxylesterase 2 to flutamide hydrolysis in human liver. Drug Metab Dispos. 40, 1080\u20131084 (2012).","journal-title":"Drug Metab Dispos."},{"issue":"6","key":"20464_CR25","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1124\/dmd.105.008516","volume":"34","author":"A Tevell","year":"2006","unstructured":"Tevell, A. et al. Flutamide metabolism in four different species in vitro and identification of flutamide metabolites in human patient urine by high performance liquid chromatography\/tandem mass spectrometry. Drug Metab Dispos. 34(6), 984\u2013992 (2006).","journal-title":"Drug Metab Dispos."},{"key":"20464_CR26","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1111\/j.1600-0773.1961.tb01655.x","volume":"17","author":"G Hollunger","year":"1960","unstructured":"Hollunger, G. On the metabolism of lidocaine II. The biotransformation of lidocaine. Acta Pharmacol Toxicol. 17, 365\u2013373 (1960).","journal-title":"the biotransformation of lidocaine. Acta Pharmacol Toxicol."},{"key":"20464_CR27","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1038\/clpt.1989.180","volume":"46","author":"MJ Bargetzi","year":"1989","unstructured":"Bargetzi, M. J., Aoyama, T., Gonzalez, F. J. & Meyer, U. A. Lidocaine metabolism in human liver microsomes by cytochrome p450IIIa4. Clin Pharmacol Ther. 46, 521\u2013527 (1989).","journal-title":"Clin Pharmacol Ther."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-20464-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-20464-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-20464-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T00:41:00Z","timestamp":1751244060000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-20464-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2,5]]},"references-count":27,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["20464"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-20464-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,2,5]]},"assertion":[{"value":"18 May 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 December 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 February 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"2405"}}