{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:33:16Z","timestamp":1787243596611,"version":"build-2736575974"},"reference-count":57,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2015,11,9]],"date-time":"2015-11-09T00:00:00Z","timestamp":1447027200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["#570968"],"award-info":[{"award-number":["#570968"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Fundamemntal Clinical Pharma"],"published-print":{"date-parts":[[2016,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Isoniazid is the first\u2010line treatment for tuberculosis; however, its use is limited by hepatotoxicity. Age\u2010related differences in isoniazid pharmacokinetics and hepatotoxicity are uncertain. We aimed to investigate these in young (3 \u00b1 0 months,\n                    <jats:italic>n<\/jats:italic>\n                    = 26) and old (23.0 \u00b1 0.2 months,\n                    <jats:italic>n<\/jats:italic>\n                    = 27) male Fischer 344 rats following a low\u2010 or high\u2010dose toxic regimen of isoniazid or vehicle (4 doses\/day over 2 days; low: 100, 75, 75, 75 mg\/kg; high: 150, 105, 105, 105 mg\/kg i.p. every 3 h). Fifteen hours after the last dose, animals were euthanized and sera and livers were prepared for analysis. Isoniazid treatment increased serum hepatotoxicity markers (alanine and aspartate transaminase) in young animals but not in old animals, and only reached significance with the high dose in young animals. Isoniazid treatment caused a trend towards an increase in necrosis in young animals with both doses. In contrast, microvesicular steatosis was increased in old isoniazid\u2010treated animals, reaching significance only with the low dose (steatosis prevalence in old: vehicle 1\/9, isoniazid 4\/5;\n                    <jats:italic>P &lt;<\/jats:italic>\n                    0.05). Among isoniazid\u2010treated animals, concentrations of toxic intermediates acetylhydrazine and hydrazine were higher in old than young animals (\n                    <jats:italic>P &lt;<\/jats:italic>\n                    0.05). With both doses, hepatic cytochrome P450 2E1 activity was higher in young animals compared with old (\n                    <jats:italic>P &lt;<\/jats:italic>\n                    0.05). There were no other age effects seen on any of the other measured enzymes involved in isoniazid metabolism (N\u2010acetyl transferase, amidase, glutathione\u2010S\u2010transferase). These results show age\u2010related changes in isoniazid pharmacokinetics may contribute towards differential patterns of toxicity and confirm that standard hepatotoxicity markers do not detect isoniazid\u2010induced microvesicular steatosis.\n                  <\/jats:p>","DOI":"10.1111\/fcp.12157","type":"journal-article","created":{"date-parts":[[2015,10,10]],"date-time":"2015-10-10T09:59:08Z","timestamp":1444471148000},"page":"23-34","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["The effect of ageing on isoniazid pharmacokinetics and hepatotoxicity in Fischer 344 rats"],"prefix":"10.1111","volume":"30","author":[{"given":"John","family":"Mach","sequence":"first","affiliation":[{"name":"Laboratory of Ageing and Pharmacology Kolling Institute of Medical Research Sydney NSW Australia"},{"name":"Department of Clin Pharmacol and Aged Care Royal North Shore Hosp Sydney NSW Australia"},{"name":"Sydney Medical School Univ of Sydney Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aniko","family":"Huizer \u2013 Pajkos","sequence":"additional","affiliation":[{"name":"Laboratory of Ageing and Pharmacology Kolling Institute of Medical Research Sydney NSW Australia"},{"name":"Department of Clin Pharmacol and Aged Care Royal North Shore Hosp Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Translational Gerontology Branch National Institute on Aging National Institute of Health Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catriona","family":"McKenzie","sequence":"additional","affiliation":[{"name":"Pathology Department Royal Prince Alfred Hosp Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo","family":"Phillips","sequence":"additional","affiliation":[{"name":"Mass Spec Imaging and Proteomics Laboratory Kolling institute of Medical Research Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Kane","sequence":"additional","affiliation":[{"name":"Laboratory of Ageing and Pharmacology Kolling Institute of Medical Research Sydney NSW Australia"},{"name":"Department of Clin Pharmacol and Aged Care Royal North Shore Hosp Sydney NSW Australia"},{"name":"Sydney Medical School Univ of Sydney Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett","family":"Jones","sequence":"additional","affiliation":[{"name":"Sydney Medical School Univ of Sydney Sydney NSW Australia"},{"name":"Department of Gastroenterology Kolling Institute of Medical Research Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"de Cabo","sequence":"additional","affiliation":[{"name":"Translational Gerontology Branch National Institute on Aging National Institute of Health Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Cogger","sequence":"additional","affiliation":[{"name":"Sydney Medical School Univ of Sydney Sydney NSW Australia"},{"name":"Ageing and Alzheimers Institute Centre for Education and Research on Ageing and Anzac Research Institute Concord Hospital and University of Sydney Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"Le Couteur","sequence":"additional","affiliation":[{"name":"Sydney Medical School Univ of Sydney Sydney NSW Australia"},{"name":"Ageing and Alzheimers Institute Centre for Education and Research on Ageing and Anzac Research Institute Concord Hospital and University of Sydney Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah N.","family":"Hilmer","sequence":"additional","affiliation":[{"name":"Laboratory of Ageing and Pharmacology Kolling Institute of Medical Research Sydney NSW Australia"},{"name":"Department of Clin Pharmacol and Aged Care Royal North Shore Hosp Sydney NSW Australia"},{"name":"Sydney Medical School Univ of Sydney Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,11,9]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"WHO.World Health Organization: Fact Sheet No.104: Tuberculosis.2015[updated 2015; cited 2015 11 March 2015]. 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