{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T06:27:37Z","timestamp":1791872857310,"version":"4.3.4"},"reference-count":24,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2012,10,9]],"date-time":"2012-10-09T00:00:00Z","timestamp":1349740800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2012,11]]},"abstract":"<jats:p><jats:bold>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT<\/jats:bold><\/jats:p><jats:p>\u2022\u2003Hepatic drug clearance is thought to be reduced with age. However for highly protein bound drugs, which are cleared by capacity\u2010limited metabolism, studies on total clearance have been conflicting. The hypothesis that protein binding decreases with age has been used to explain this.<\/jats:p><jats:p>\u2022\u2003Warfarin is a highly protein bound drug, which is cleared by capacity\u2010limited metabolism. There are conflicting or little data on the relationship between adult age and total and free clearance and protein binding of (R)\u2010 and (S)\u2010warfarin.<\/jats:p><jats:p><jats:bold>WHAT THIS STUDY ADDS<\/jats:bold><\/jats:p><jats:p>\u2022\u2003In a clinical study of 72 patients (18\u201389 years) on warfarin therapy, both total and free clearance of (R)\u2010warfarin decreased with age. For (S)\u2010warfarin there was a stronger signal of a decrease in free than total clearance. Protein binding was found not to correlate with age for (R)\u2010 and (S)\u2010warfarin.<\/jats:p><jats:p>\u2022\u2003In an <jats:italic>ex vivo<\/jats:italic> study, in which warfarin was spiked to plasma samples from 60 healthy subjects (19\u201387 years), no correlation between protein binding and age was found.<\/jats:p><jats:p>\u2022\u2003These data support the hypothesis that hepatic drug clearance decreases with age. This should be taken into consideration when individualizing dosing, particularly in the elderly.<\/jats:p><jats:p><jats:bold>AIMS<\/jats:bold> To test the hypothesis that the clearance (CL) of warfarin, a very highly protein bound drug with capacity\u2010limited metabolism, decreases with age.<\/jats:p><jats:p><jats:bold>METHODS<\/jats:bold> In a clinical study, a steady\u2010state blood sample was taken from 72 patients (18\u201389 years) on routine treatment with warfarin. Concentrations of (R)\u2010 and (S)\u2010warfarin were determined in plasma (total) and ultrafiltrate (free) by LC\u2010MS\/MS. Total and free CL and protein binding were determined and regressed against age and other covariates. In an <jats:italic>ex vivo<\/jats:italic> study, warfarin was spiked to plasma samples from 60 healthy subjects (19\u201387 years) and protein binding was regressed against age and other covariates.<\/jats:p><jats:p><jats:bold>RESULTS<\/jats:bold> For (R)\u2010warfarin a significant decrease with age was found for both total and free CL (<jats:italic>P<\/jats:italic> &lt; 0.001). For (S)\u2010warfarin there was a stronger signal of a decrease with age in free CL (<jats:italic>P<\/jats:italic>= 0.005) <jats:italic>vs.<\/jats:italic> total CL (<jats:italic>P<\/jats:italic>= 0.045). The decrease in CL of (R)\u2010 and (S)\u2010warfarin was 0.3\u20130.5% per year. Other covariates influencing CL were lean body weight for both (R)\u2010 and (S)\u2010warfarin and <jats:italic>CYP2C9<\/jats:italic> genotype and blood sampling time for (S)\u2010warfarin. Protein binding of (R)\u2010 and (S)\u2010warfarin was not found to change significantly with age in either the clinical or the spiked samples, despite a slight decrease in albumin concentration with age.<\/jats:p><jats:p><jats:bold>CONCLUSIONS<\/jats:bold> These data support the hypothesis that the CL of (R)\u2010 and (S)\u2010warfarin decreases with age. More accurate information was gained when measuring free CL for (S)\u2010warfarin. Warfarin protein binding did not change significantly with age.<\/jats:p>","DOI":"10.1111\/j.1365-2125.2012.04259.x","type":"journal-article","created":{"date-parts":[[2012,3,1]],"date-time":"2012-03-01T16:43:13Z","timestamp":1330620193000},"page":"797-805","source":"Crossref","is-referenced-by-count":30,"title":["Influence of adult age on the total and free clearance and protein binding of (R)\u2010 and (S)\u2010warfarin"],"prefix":"10.1111","volume":"74","author":[{"given":"Berit Packert","family":"Jensen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul Ken Leong","family":"Chin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca Lee","family":"Roberts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan James","family":"Begg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,10,9]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.56.2.4"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200847050-00002"},{"key":"e_1_2_7_4_2","volume-title":"Therapeutic Drugs","author":"Dollery C","year":"1999"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1979.tb01009.x"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01065653"},{"key":"e_1_2_7_7_2","first-page":"203","article-title":"The influence of age, liver size and enantiomer concentrations on warfarin requirements","volume":"40","author":"Wynne H","year":"1995","journal-title":"Br J Clin Pharmacol"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1067\/mcp.2001.117444"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2003.10.001"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-03-1108"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.tpj.6500308"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1977.tb00719.x"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1994.tb04305.x"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1681.1978.tb00664.x"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1975.tb00474.x"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1982.186"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2011.04036.x"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00216-011-5303-x"},{"key":"e_1_2_7_19_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200544100-00004"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-145-4-200608150-00004"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.2217\/pgs.10.49"},{"key":"e_1_2_7_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.clpt.6100084"},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2010.37"},{"key":"e_1_2_7_24_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2011.04051.x"},{"key":"e_1_2_7_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)39899-0"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fj.1365-2125.2012.04259.x","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/j.1365-2125.2012.04259.x","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,23]],"date-time":"2023-09-23T23:09:22Z","timestamp":1695510562000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/j.1365-2125.2012.04259.x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,10,9]]},"references-count":24,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2012,11]]}},"alternative-id":["10.1111\/j.1365-2125.2012.04259.x"],"URL":"https:\/\/doi.org\/10.1111\/j.1365-2125.2012.04259.x","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"value":"0306-5251","type":"print"},{"value":"1365-2125","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,10,9]]}}}