{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:26:18Z","timestamp":1790623578409,"version":"4.1.0"},"reference-count":29,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2012,7,10]],"date-time":"2012-07-10T00:00:00Z","timestamp":1341878400000},"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":[[2012,8]]},"abstract":"<jats:p><jats:bold>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT<\/jats:bold><\/jats:p><jats:p>\u2022\u2003(R,S)\u2010ketamine is a phencyclidine derivative that was initially developed as an anaesthetic agent and which is currently being studied in the treatment of pain and depression. After administration, the drug is extensively N\u2010demethylated to (R,S)\u2010norketamine. The pharmacokinetics of ketamine and norketamine have been extensively studied in volunteers and patients after the administration of anaesthetic and sub\u2010anaesthetic doses. However, ketamine and norketamine are extensively transformed into a series of diastereomeric hydroxyketamines and hydroxynorketamines and (R,S)\u2010dehydronorketamine metabolites. The plasma kinetics of these metabolites have not been elucidated.<\/jats:p><jats:p><jats:bold>WHAT THIS STUDY ADDS<\/jats:bold><\/jats:p><jats:p>\u2022\u2003The current study expands the characterization of the disposition kinetics of (R,S)\u2010ketamine and (R,S)\u2010norketamine and presents a population pharmacokinetic analysis of (R)\u2010ketamine, (S)\u2010ketamine, (R)\u2010norketamine, (S)\u2010norketamine, (R)\u2010dehydronorketamine, (S)\u2010 dehydronorketamine and (2S,6S;2R,6R)\u2010hydroxynorketamine and the serum concentration\u2013time profiles of multiple ketamine metabolites observed in the plasma of patients after a single 40\u2003min infusion of a sub\u2010anaesthetic dose of the drug. The data demonstrate that while norketamine is an initial metabolite, it is not the major circulating metabolite and suggest that the determination of the downstream metabolites of ketamine may play a role in the pharmacological effects of the drug.<\/jats:p><jats:p><jats:bold>AIM<\/jats:bold> To construct a population pharmacokinetic (popPK) model for ketamine (Ket), norketamine (norKet), dehydronorketamine (DHNK), hydroxynorketamine (2S,6S;2R,6R)\u2010HNK) and hydroxyketamine (HK) in patients with treatment\u2010resistant bipolar depression.<\/jats:p><jats:p><jats:bold>METHOD<\/jats:bold> Plasma samples were collected at 40, 80, 110, 230\u2003min on day 1, 2 and 3 in nine patients following a 40\u2003min infusion of (R,S)\u2010Ket (0.5\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup>) and analyzed for Ket, norKet and DHNK enantiomers and (2S,6S;2R,6R)\u2010HNK, (2S,6S;2R,6R)\u2010HK and (2S,6R;2R,6S)\u2010HK. A compartmental popPK model was constructed that included all quantified analytes, and unknown parameters were estimated with an iterative two\u2010stage algorithm in ADAPT5.<\/jats:p><jats:p><jats:bold>RESULTS<\/jats:bold> Ket, norKet, DHNK and (2S,6S;2R,6R)\u2010HNK were present during the first 230\u2003min post infusion and significant concentrations (&gt;5\u2003ng\u2003ml<jats:sup>\u22121<\/jats:sup>) were observed on day 1. Plasma concentrations of (2S,6S;2R,6R)\u2010HK and (2S,6R;2R,6S)\u2010HK were below the limit of quantification. The average (S)\u2003:\u2003(R) plasma concentrations for Ket and DHNK were &lt;1.0 while no significant enantioselectivity was observed for norKet. There were large inter\u2010patient variations in terminal half\u2010lives and relative metabolite concentrations; at 230\u2003min (R,S)\u2010DHNK was the major metabolite in four out of nine patients, (R,S)\u2010norKet in three out of nine patients and (2S,6S;2R,6R)\u2010HNK in two out of nine patients. The final PK model included three compartments for (R,S)\u2010Ket, two compartments for (R,S)\u2010norKet and single compartments for DHNK and HNK. All PK profiles were well described, and parameters for (R,S)\u2010Ket and (R,S)\u2010norKet were in agreement with prior estimates.<\/jats:p><jats:p><jats:bold>CONCLUSION<\/jats:bold> This represents the first PK analysis of (2S,6S;2R,6R)\u2010HNK and (R,S)\u2010DHNK. The results demonstrate that while norKet is the initial metabolite, it is not the main metabolite suggesting that future Ket studies should include the analysis of the major metabolites.<\/jats:p>","DOI":"10.1111\/j.1365-2125.2012.04198.x","type":"journal-article","created":{"date-parts":[[2012,2,1]],"date-time":"2012-02-01T17:55:24Z","timestamp":1328118924000},"page":"304-314","source":"Crossref","is-referenced-by-count":129,"title":["Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment\u2010resistant bipolar depression"],"prefix":"10.1111","volume":"74","author":[{"given":"Xiaochen","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swarajya Lakshmi Vattem","family":"Venkata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruin","family":"Moaddel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dave A.","family":"Luckenbaugh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy E.","family":"Brutsche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lobna","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos A.","family":"Zarate Jr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald E.","family":"Mager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irving W.","family":"Wainer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,7,10]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1213\/00000539-199811000-00039"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e3181ed09a2"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1586\/ern.11.31"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11916-011-0185-3"},{"key":"e_1_2_7_6_2","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1097\/ALN.0b013e3181e90914","article-title":"Intraoperative ketamine reduces perioperative opiate consumption in opiate\u2010dependent patients with chronic back pain undergoing back surgery","volume":"113","author":"Loftus RW","year":"2010","journal-title":"Anesthesiology"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajem.2009.07.023"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.63.8.856"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1001\/archgenpsychiatry.2010.90"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.09m05327blu"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2009.06.023"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e3181b437b1"},{"key":"e_1_2_7_13_2","first-page":"258","article-title":"Population pharmacokinetic\u2010pharamcodynamic modeling of ketamine\u2010induced pain relief of chronic pain. 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