Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment‐resistant bipolar depression
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • (R,S)‐ketamine 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‐demethylated to (R,S)‐norketamine...
Gespeichert in:
| Veröffentlicht in: | British journal of clinical pharmacology 2012-08, Vol.74 (2), p.304-314 |
|---|---|
| Hauptverfasser: | , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 314 |
|---|---|
| container_issue | 2 |
| container_start_page | 304 |
| container_title | British journal of clinical pharmacology |
| container_volume | 74 |
| creator | Zhao, Xiaochen Venkata, Swarajya Lakshmi Vattem Moaddel, Ruin Luckenbaugh, Dave A. Brutsche, Nancy E. Ibrahim, Lobna Zarate Jr, Carlos A. Mager, Donald E. Wainer, Irving W. |
| description | WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• (R,S)‐ketamine 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‐demethylated to (R,S)‐norketamine. The pharmacokinetics of ketamine and norketamine have been extensively studied in volunteers and patients after the administration of anaesthetic and sub‐anaesthetic doses. However, ketamine and norketamine are extensively transformed into a series of diastereomeric hydroxyketamines and hydroxynorketamines and (R,S)‐dehydronorketamine metabolites. The plasma kinetics of these metabolites have not been elucidated.
WHAT THIS STUDY ADDS
• The current study expands the characterization of the disposition kinetics of (R,S)‐ketamine and (R,S)‐norketamine and presents a population pharmacokinetic analysis of (R)‐ketamine, (S)‐ketamine, (R)‐norketamine, (S)‐norketamine, (R)‐dehydronorketamine, (S)‐ dehydronorketamine and (2S,6S;2R,6R)‐hydroxynorketamine and the serum concentration–time profiles of multiple ketamine metabolites observed in the plasma of patients after a single 40 min infusion of a sub‐anaesthetic 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.
AIM To construct a population pharmacokinetic (popPK) model for ketamine (Ket), norketamine (norKet), dehydronorketamine (DHNK), hydroxynorketamine (2S,6S;2R,6R)‐HNK) and hydroxyketamine (HK) in patients with treatment‐resistant bipolar depression.
METHOD Plasma samples were collected at 40, 80, 110, 230 min on day 1, 2 and 3 in nine patients following a 40 min infusion of (R,S)‐Ket (0.5 mg kg−1) and analyzed for Ket, norKet and DHNK enantiomers and (2S,6S;2R,6R)‐HNK, (2S,6S;2R,6R)‐HK and (2S,6R;2R,6S)‐HK. A compartmental popPK model was constructed that included all quantified analytes, and unknown parameters were estimated with an iterative two‐stage algorithm in ADAPT5.
RESULTS Ket, norKet, DHNK and (2S,6S;2R,6R)‐HNK were present during the first 230 min post infusion and significant concentrations (>5 ng ml−1) were observed on day 1. Plasma concentrations of (2S,6S;2R,6R)‐HK and (2S,6R;2R,6S)‐HK were below the limit of quantification. The average (S) : (R) plasma concentrations for Ket and DHN |
| doi_str_mv | 10.1111/j.1365-2125.2012.04198.x |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3630750</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1837347045</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5378-376ddf64206c8c6eda9a541e5a4821bda183795a2217f9cde49508c2ec37f1783</originalsourceid><addsrcrecordid>eNqNUcuO1DAQtBCIHRZ-AfmCxCXBjziPA0gwggVpJZCAs9XjODueteNgO-zujU9A4g_3S3CYYYAbvtjtqq4udSGEKSlpPs92JeW1KBhlomSEspJUtGvL6ztodQTuohXhpC4EE_QEPYhxRwjltBb30QljrBNtJ1box0fjZptg1H6OePLTbCEZP-JpC8GB8pdm1Mko7HyvrTXjBfYDvtQJXAYwjD1O26A1drDzAbsMbLw1SUdsskjW0mOK-MqkLU5BQ3K5vv32PehoYh6b8MZM3kLAvZ7yZ8yzH6J7A9ioHx3uU_T5zetP67fF-fuzd-uX54USvGkL3tR9P9QVI7VqVa176EBUVAuoWkY3PdCWN50AxmgzdKrXVSdIq5hWvBlo0_JT9GKvO80bp3uVnQWwcgrGQbiRHoz8FxnNVl74r5LXnDSCZIGnB4Hgv8w6JulMVHlN-3XKxQCvGlKJTG33VBV8jEEPxzGUyCVTuZNLdHKJTi6Zyl-Zyuvc-vhvm8fG3yFmwpMDAaICOwQYlYl_eDVlHSUs857veVfG6pv_NiBfrT8sL_4TVuPDsw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1837347045</pqid></control><display><type>article</type><title>Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment‐resistant bipolar depression</title><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><source>Wiley Online Library Free Content</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Zhao, Xiaochen ; Venkata, Swarajya Lakshmi Vattem ; Moaddel, Ruin ; Luckenbaugh, Dave A. ; Brutsche, Nancy E. ; Ibrahim, Lobna ; Zarate Jr, Carlos A. ; Mager, Donald E. ; Wainer, Irving W.</creator><creatorcontrib>Zhao, Xiaochen ; Venkata, Swarajya Lakshmi Vattem ; Moaddel, Ruin ; Luckenbaugh, Dave A. ; Brutsche, Nancy E. ; Ibrahim, Lobna ; Zarate Jr, Carlos A. ; Mager, Donald E. ; Wainer, Irving W.</creatorcontrib><description>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• (R,S)‐ketamine 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‐demethylated to (R,S)‐norketamine. The pharmacokinetics of ketamine and norketamine have been extensively studied in volunteers and patients after the administration of anaesthetic and sub‐anaesthetic doses. However, ketamine and norketamine are extensively transformed into a series of diastereomeric hydroxyketamines and hydroxynorketamines and (R,S)‐dehydronorketamine metabolites. The plasma kinetics of these metabolites have not been elucidated.
WHAT THIS STUDY ADDS
• The current study expands the characterization of the disposition kinetics of (R,S)‐ketamine and (R,S)‐norketamine and presents a population pharmacokinetic analysis of (R)‐ketamine, (S)‐ketamine, (R)‐norketamine, (S)‐norketamine, (R)‐dehydronorketamine, (S)‐ dehydronorketamine and (2S,6S;2R,6R)‐hydroxynorketamine and the serum concentration–time profiles of multiple ketamine metabolites observed in the plasma of patients after a single 40 min infusion of a sub‐anaesthetic 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.
AIM To construct a population pharmacokinetic (popPK) model for ketamine (Ket), norketamine (norKet), dehydronorketamine (DHNK), hydroxynorketamine (2S,6S;2R,6R)‐HNK) and hydroxyketamine (HK) in patients with treatment‐resistant bipolar depression.
METHOD Plasma samples were collected at 40, 80, 110, 230 min on day 1, 2 and 3 in nine patients following a 40 min infusion of (R,S)‐Ket (0.5 mg kg−1) and analyzed for Ket, norKet and DHNK enantiomers and (2S,6S;2R,6R)‐HNK, (2S,6S;2R,6R)‐HK and (2S,6R;2R,6S)‐HK. A compartmental popPK model was constructed that included all quantified analytes, and unknown parameters were estimated with an iterative two‐stage algorithm in ADAPT5.
RESULTS Ket, norKet, DHNK and (2S,6S;2R,6R)‐HNK were present during the first 230 min post infusion and significant concentrations (>5 ng ml−1) were observed on day 1. Plasma concentrations of (2S,6S;2R,6R)‐HK and (2S,6R;2R,6S)‐HK were below the limit of quantification. The average (S) : (R) plasma concentrations for Ket and DHNK were <1.0 while no significant enantioselectivity was observed for norKet. There were large inter‐patient variations in terminal half‐lives and relative metabolite concentrations; at 230 min (R,S)‐DHNK was the major metabolite in four out of nine patients, (R,S)‐norKet in three out of nine patients and (2S,6S;2R,6R)‐HNK in two out of nine patients. The final PK model included three compartments for (R,S)‐Ket, two compartments for (R,S)‐norKet and single compartments for DHNK and HNK. All PK profiles were well described, and parameters for (R,S)‐Ket and (R,S)‐norKet were in agreement with prior estimates.
CONCLUSION This represents the first PK analysis of (2S,6S;2R,6R)‐HNK and (R,S)‐DHNK. 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.</description><identifier>ISSN: 0306-5251</identifier><identifier>EISSN: 1365-2125</identifier><identifier>DOI: 10.1111/j.1365-2125.2012.04198.x</identifier><identifier>PMID: 22295895</identifier><identifier>CODEN: BCPHBM</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>(2S, 6S;2R, 6R)‐hydroxynorketamine ; (R, S)‐dehydronorketamine ; (R, S)‐norketamine ; Adult ; Adult and adolescent clinical studies ; Algorithms ; Antidepressive Agents - administration & dosage ; Antidepressive Agents - blood ; Antidepressive Agents - pharmacokinetics ; Biological and medical sciences ; Biotransformation ; bipolar depression ; Bipolar Disorder - blood ; Bipolar Disorder - drug therapy ; Bipolar disorders ; Cross-Over Studies ; Depression ; Double-Blind Method ; Drug Resistance ; Female ; Humans ; Hydroxylation ; Infusions, Parenteral ; Ketamine - administration & dosage ; Ketamine - analogs & derivatives ; Ketamine - blood ; Ketamine - pharmacokinetics ; Male ; Medical sciences ; Middle Aged ; Models, Biological ; Mood disorders ; Pharmacokinetics ; Pharmacology. Drug treatments ; Psychology. Psychoanalysis. Psychiatry ; Psychopathology. Psychiatry ; stereoselectivity ; Young Adult</subject><ispartof>British journal of clinical pharmacology, 2012-08, Vol.74 (2), p.304-314</ispartof><rights>Published 2012. This article is a U.S. Government work and is in the public domain in the USA</rights><rights>2015 INIST-CNRS</rights><rights>Published 2012. This article is a U.S. Government work and is in the public domain in the USA.</rights><rights>Copyright © 2012 The British Pharmacological Society 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5378-376ddf64206c8c6eda9a541e5a4821bda183795a2217f9cde49508c2ec37f1783</citedby><cites>FETCH-LOGICAL-c5378-376ddf64206c8c6eda9a541e5a4821bda183795a2217f9cde49508c2ec37f1783</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1365-2125.2012.04198.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1365-2125.2012.04198.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,776,780,881,1411,1427,27903,27904,45553,45554,46387,46811</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26129102$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22295895$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhao, Xiaochen</creatorcontrib><creatorcontrib>Venkata, Swarajya Lakshmi Vattem</creatorcontrib><creatorcontrib>Moaddel, Ruin</creatorcontrib><creatorcontrib>Luckenbaugh, Dave A.</creatorcontrib><creatorcontrib>Brutsche, Nancy E.</creatorcontrib><creatorcontrib>Ibrahim, Lobna</creatorcontrib><creatorcontrib>Zarate Jr, Carlos A.</creatorcontrib><creatorcontrib>Mager, Donald E.</creatorcontrib><creatorcontrib>Wainer, Irving W.</creatorcontrib><title>Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment‐resistant bipolar depression</title><title>British journal of clinical pharmacology</title><addtitle>Br J Clin Pharmacol</addtitle><description>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• (R,S)‐ketamine 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‐demethylated to (R,S)‐norketamine. The pharmacokinetics of ketamine and norketamine have been extensively studied in volunteers and patients after the administration of anaesthetic and sub‐anaesthetic doses. However, ketamine and norketamine are extensively transformed into a series of diastereomeric hydroxyketamines and hydroxynorketamines and (R,S)‐dehydronorketamine metabolites. The plasma kinetics of these metabolites have not been elucidated.
WHAT THIS STUDY ADDS
• The current study expands the characterization of the disposition kinetics of (R,S)‐ketamine and (R,S)‐norketamine and presents a population pharmacokinetic analysis of (R)‐ketamine, (S)‐ketamine, (R)‐norketamine, (S)‐norketamine, (R)‐dehydronorketamine, (S)‐ dehydronorketamine and (2S,6S;2R,6R)‐hydroxynorketamine and the serum concentration–time profiles of multiple ketamine metabolites observed in the plasma of patients after a single 40 min infusion of a sub‐anaesthetic 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.
AIM To construct a population pharmacokinetic (popPK) model for ketamine (Ket), norketamine (norKet), dehydronorketamine (DHNK), hydroxynorketamine (2S,6S;2R,6R)‐HNK) and hydroxyketamine (HK) in patients with treatment‐resistant bipolar depression.
METHOD Plasma samples were collected at 40, 80, 110, 230 min on day 1, 2 and 3 in nine patients following a 40 min infusion of (R,S)‐Ket (0.5 mg kg−1) and analyzed for Ket, norKet and DHNK enantiomers and (2S,6S;2R,6R)‐HNK, (2S,6S;2R,6R)‐HK and (2S,6R;2R,6S)‐HK. A compartmental popPK model was constructed that included all quantified analytes, and unknown parameters were estimated with an iterative two‐stage algorithm in ADAPT5.
RESULTS Ket, norKet, DHNK and (2S,6S;2R,6R)‐HNK were present during the first 230 min post infusion and significant concentrations (>5 ng ml−1) were observed on day 1. Plasma concentrations of (2S,6S;2R,6R)‐HK and (2S,6R;2R,6S)‐HK were below the limit of quantification. The average (S) : (R) plasma concentrations for Ket and DHNK were <1.0 while no significant enantioselectivity was observed for norKet. There were large inter‐patient variations in terminal half‐lives and relative metabolite concentrations; at 230 min (R,S)‐DHNK was the major metabolite in four out of nine patients, (R,S)‐norKet in three out of nine patients and (2S,6S;2R,6R)‐HNK in two out of nine patients. The final PK model included three compartments for (R,S)‐Ket, two compartments for (R,S)‐norKet and single compartments for DHNK and HNK. All PK profiles were well described, and parameters for (R,S)‐Ket and (R,S)‐norKet were in agreement with prior estimates.
CONCLUSION This represents the first PK analysis of (2S,6S;2R,6R)‐HNK and (R,S)‐DHNK. 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.</description><subject>(2S, 6S;2R, 6R)‐hydroxynorketamine</subject><subject>(R, S)‐dehydronorketamine</subject><subject>(R, S)‐norketamine</subject><subject>Adult</subject><subject>Adult and adolescent clinical studies</subject><subject>Algorithms</subject><subject>Antidepressive Agents - administration & dosage</subject><subject>Antidepressive Agents - blood</subject><subject>Antidepressive Agents - pharmacokinetics</subject><subject>Biological and medical sciences</subject><subject>Biotransformation</subject><subject>bipolar depression</subject><subject>Bipolar Disorder - blood</subject><subject>Bipolar Disorder - drug therapy</subject><subject>Bipolar disorders</subject><subject>Cross-Over Studies</subject><subject>Depression</subject><subject>Double-Blind Method</subject><subject>Drug Resistance</subject><subject>Female</subject><subject>Humans</subject><subject>Hydroxylation</subject><subject>Infusions, Parenteral</subject><subject>Ketamine - administration & dosage</subject><subject>Ketamine - analogs & derivatives</subject><subject>Ketamine - blood</subject><subject>Ketamine - pharmacokinetics</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Models, Biological</subject><subject>Mood disorders</subject><subject>Pharmacokinetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Psychology. Psychoanalysis. Psychiatry</subject><subject>Psychopathology. Psychiatry</subject><subject>stereoselectivity</subject><subject>Young Adult</subject><issn>0306-5251</issn><issn>1365-2125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNUcuO1DAQtBCIHRZ-AfmCxCXBjziPA0gwggVpJZCAs9XjODueteNgO-zujU9A4g_3S3CYYYAbvtjtqq4udSGEKSlpPs92JeW1KBhlomSEspJUtGvL6ztodQTuohXhpC4EE_QEPYhxRwjltBb30QljrBNtJ1box0fjZptg1H6OePLTbCEZP-JpC8GB8pdm1Mko7HyvrTXjBfYDvtQJXAYwjD1O26A1drDzAbsMbLw1SUdsskjW0mOK-MqkLU5BQ3K5vv32PehoYh6b8MZM3kLAvZ7yZ8yzH6J7A9ioHx3uU_T5zetP67fF-fuzd-uX54USvGkL3tR9P9QVI7VqVa176EBUVAuoWkY3PdCWN50AxmgzdKrXVSdIq5hWvBlo0_JT9GKvO80bp3uVnQWwcgrGQbiRHoz8FxnNVl74r5LXnDSCZIGnB4Hgv8w6JulMVHlN-3XKxQCvGlKJTG33VBV8jEEPxzGUyCVTuZNLdHKJTi6Zyl-Zyuvc-vhvm8fG3yFmwpMDAaICOwQYlYl_eDVlHSUs857veVfG6pv_NiBfrT8sL_4TVuPDsw</recordid><startdate>201208</startdate><enddate>201208</enddate><creator>Zhao, Xiaochen</creator><creator>Venkata, Swarajya Lakshmi Vattem</creator><creator>Moaddel, Ruin</creator><creator>Luckenbaugh, Dave A.</creator><creator>Brutsche, Nancy E.</creator><creator>Ibrahim, Lobna</creator><creator>Zarate Jr, Carlos A.</creator><creator>Mager, Donald E.</creator><creator>Wainer, Irving W.</creator><general>Blackwell Publishing Ltd</general><general>Blackwell</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7U7</scope><scope>C1K</scope><scope>5PM</scope></search><sort><creationdate>201208</creationdate><title>Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment‐resistant bipolar depression</title><author>Zhao, Xiaochen ; Venkata, Swarajya Lakshmi Vattem ; Moaddel, Ruin ; Luckenbaugh, Dave A. ; Brutsche, Nancy E. ; Ibrahim, Lobna ; Zarate Jr, Carlos A. ; Mager, Donald E. ; Wainer, Irving W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5378-376ddf64206c8c6eda9a541e5a4821bda183795a2217f9cde49508c2ec37f1783</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>(2S, 6S;2R, 6R)‐hydroxynorketamine</topic><topic>(R, S)‐dehydronorketamine</topic><topic>(R, S)‐norketamine</topic><topic>Adult</topic><topic>Adult and adolescent clinical studies</topic><topic>Algorithms</topic><topic>Antidepressive Agents - administration & dosage</topic><topic>Antidepressive Agents - blood</topic><topic>Antidepressive Agents - pharmacokinetics</topic><topic>Biological and medical sciences</topic><topic>Biotransformation</topic><topic>bipolar depression</topic><topic>Bipolar Disorder - blood</topic><topic>Bipolar Disorder - drug therapy</topic><topic>Bipolar disorders</topic><topic>Cross-Over Studies</topic><topic>Depression</topic><topic>Double-Blind Method</topic><topic>Drug Resistance</topic><topic>Female</topic><topic>Humans</topic><topic>Hydroxylation</topic><topic>Infusions, Parenteral</topic><topic>Ketamine - administration & dosage</topic><topic>Ketamine - analogs & derivatives</topic><topic>Ketamine - blood</topic><topic>Ketamine - pharmacokinetics</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Models, Biological</topic><topic>Mood disorders</topic><topic>Pharmacokinetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Psychology. Psychoanalysis. Psychiatry</topic><topic>Psychopathology. Psychiatry</topic><topic>stereoselectivity</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhao, Xiaochen</creatorcontrib><creatorcontrib>Venkata, Swarajya Lakshmi Vattem</creatorcontrib><creatorcontrib>Moaddel, Ruin</creatorcontrib><creatorcontrib>Luckenbaugh, Dave A.</creatorcontrib><creatorcontrib>Brutsche, Nancy E.</creatorcontrib><creatorcontrib>Ibrahim, Lobna</creatorcontrib><creatorcontrib>Zarate Jr, Carlos A.</creatorcontrib><creatorcontrib>Mager, Donald E.</creatorcontrib><creatorcontrib>Wainer, Irving W.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhao, Xiaochen</au><au>Venkata, Swarajya Lakshmi Vattem</au><au>Moaddel, Ruin</au><au>Luckenbaugh, Dave A.</au><au>Brutsche, Nancy E.</au><au>Ibrahim, Lobna</au><au>Zarate Jr, Carlos A.</au><au>Mager, Donald E.</au><au>Wainer, Irving W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment‐resistant bipolar depression</atitle><jtitle>British journal of clinical pharmacology</jtitle><addtitle>Br J Clin Pharmacol</addtitle><date>2012-08</date><risdate>2012</risdate><volume>74</volume><issue>2</issue><spage>304</spage><epage>314</epage><pages>304-314</pages><issn>0306-5251</issn><eissn>1365-2125</eissn><coden>BCPHBM</coden><abstract>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• (R,S)‐ketamine 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‐demethylated to (R,S)‐norketamine. The pharmacokinetics of ketamine and norketamine have been extensively studied in volunteers and patients after the administration of anaesthetic and sub‐anaesthetic doses. However, ketamine and norketamine are extensively transformed into a series of diastereomeric hydroxyketamines and hydroxynorketamines and (R,S)‐dehydronorketamine metabolites. The plasma kinetics of these metabolites have not been elucidated.
WHAT THIS STUDY ADDS
• The current study expands the characterization of the disposition kinetics of (R,S)‐ketamine and (R,S)‐norketamine and presents a population pharmacokinetic analysis of (R)‐ketamine, (S)‐ketamine, (R)‐norketamine, (S)‐norketamine, (R)‐dehydronorketamine, (S)‐ dehydronorketamine and (2S,6S;2R,6R)‐hydroxynorketamine and the serum concentration–time profiles of multiple ketamine metabolites observed in the plasma of patients after a single 40 min infusion of a sub‐anaesthetic 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.
AIM To construct a population pharmacokinetic (popPK) model for ketamine (Ket), norketamine (norKet), dehydronorketamine (DHNK), hydroxynorketamine (2S,6S;2R,6R)‐HNK) and hydroxyketamine (HK) in patients with treatment‐resistant bipolar depression.
METHOD Plasma samples were collected at 40, 80, 110, 230 min on day 1, 2 and 3 in nine patients following a 40 min infusion of (R,S)‐Ket (0.5 mg kg−1) and analyzed for Ket, norKet and DHNK enantiomers and (2S,6S;2R,6R)‐HNK, (2S,6S;2R,6R)‐HK and (2S,6R;2R,6S)‐HK. A compartmental popPK model was constructed that included all quantified analytes, and unknown parameters were estimated with an iterative two‐stage algorithm in ADAPT5.
RESULTS Ket, norKet, DHNK and (2S,6S;2R,6R)‐HNK were present during the first 230 min post infusion and significant concentrations (>5 ng ml−1) were observed on day 1. Plasma concentrations of (2S,6S;2R,6R)‐HK and (2S,6R;2R,6S)‐HK were below the limit of quantification. The average (S) : (R) plasma concentrations for Ket and DHNK were <1.0 while no significant enantioselectivity was observed for norKet. There were large inter‐patient variations in terminal half‐lives and relative metabolite concentrations; at 230 min (R,S)‐DHNK was the major metabolite in four out of nine patients, (R,S)‐norKet in three out of nine patients and (2S,6S;2R,6R)‐HNK in two out of nine patients. The final PK model included three compartments for (R,S)‐Ket, two compartments for (R,S)‐norKet and single compartments for DHNK and HNK. All PK profiles were well described, and parameters for (R,S)‐Ket and (R,S)‐norKet were in agreement with prior estimates.
CONCLUSION This represents the first PK analysis of (2S,6S;2R,6R)‐HNK and (R,S)‐DHNK. 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.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>22295895</pmid><doi>10.1111/j.1365-2125.2012.04198.x</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0306-5251 |
| ispartof | British journal of clinical pharmacology, 2012-08, Vol.74 (2), p.304-314 |
| issn | 0306-5251 1365-2125 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3630750 |
| source | MEDLINE; Wiley Online Library Journals Frontfile Complete; Wiley Online Library Free Content; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | (2S, 6S 2R, 6R)‐hydroxynorketamine (R, S)‐dehydronorketamine (R, S)‐norketamine Adult Adult and adolescent clinical studies Algorithms Antidepressive Agents - administration & dosage Antidepressive Agents - blood Antidepressive Agents - pharmacokinetics Biological and medical sciences Biotransformation bipolar depression Bipolar Disorder - blood Bipolar Disorder - drug therapy Bipolar disorders Cross-Over Studies Depression Double-Blind Method Drug Resistance Female Humans Hydroxylation Infusions, Parenteral Ketamine - administration & dosage Ketamine - analogs & derivatives Ketamine - blood Ketamine - pharmacokinetics Male Medical sciences Middle Aged Models, Biological Mood disorders Pharmacokinetics Pharmacology. Drug treatments Psychology. Psychoanalysis. Psychiatry Psychopathology. Psychiatry stereoselectivity Young Adult |
| title | Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment‐resistant bipolar depression |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T12%3A42%3A07IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Simultaneous%20population%20pharmacokinetic%20modelling%20of%20ketamine%20and%20three%20major%20metabolites%20in%20patients%20with%20treatment%E2%80%90resistant%20bipolar%20depression&rft.jtitle=British%20journal%20of%20clinical%20pharmacology&rft.au=Zhao,%20Xiaochen&rft.date=2012-08&rft.volume=74&rft.issue=2&rft.spage=304&rft.epage=314&rft.pages=304-314&rft.issn=0306-5251&rft.eissn=1365-2125&rft.coden=BCPHBM&rft_id=info:doi/10.1111/j.1365-2125.2012.04198.x&rft_dat=%3Cproquest_pubme%3E1837347045%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1837347045&rft_id=info:pmid/22295895&rfr_iscdi=true |