No significant influence of OCT1 genotypes on the pharmacokinetics of morphine in adult surgical patients
We investigated the impact of genetic variants in OCT1 (SLC22A1) on morphine, morphine‐3‐glucuronide (M3G) and morphine‐6‐glucuronide (M6G) pharmacokinetics in adult patients scheduled for major surgery. Blood samples were taken before and 5, 10, 15, 30, 45, 60 and 90 min after a bolus of morphine (...
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| Veröffentlicht in: | Basic & clinical pharmacology & toxicology 2022-01, Vol.130 (1), p.93-102 |
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| creator | Kuhlmann, Ida Hjelmar Petersen, Rasmus Overgaard, Morten Dornonville de la Cour, Kenn Zwisler, Stine Bjerregaard Stage, Tore Hougaard Christensen, Mette Marie Bergmann, Troels K. Damkier, Per Gadegaard Jensen, Anders Nielsen, Flemming Brøsen, Kim |
| description | We investigated the impact of genetic variants in OCT1 (SLC22A1) on morphine, morphine‐3‐glucuronide (M3G) and morphine‐6‐glucuronide (M6G) pharmacokinetics in adult patients scheduled for major surgery. Blood samples were taken before and 5, 10, 15, 30, 45, 60 and 90 min after a bolus of morphine (0.15 mg/kg). Patients were genotyped for the genetic variants (rs12208357, rs34059508, rs72552763 and rs34130495) in OCT1.
Eighty‐six patients completed the trial. The mean difference (95% confidence interval) for dose adjusted morphine, M3G and M6G AUC was 0.9 (−0.7–2.4), −5.9 (−11.8 to −0.03) and −1.1 (−2.5–0.4) h/L*10−6, respectively, in patients with two reduced function alleles compared to patients with no reduced function alleles in OCT1. Accordingly, the (AUCM3G/Dose)/(AUCmorphine/Dose) and (AUCM6G/Dose)/(AUCmorphine/Dose) ratio was reduced, −1.8 (−3.2 to −0.4) and −0.4 (−0.7 to −0.03), respectively, when comparing the same groups. OCT1 variants had no influence on the experience of pain, adverse events or the number of PCA doses used. In conclusion, genetic variants in OCT1 had a small and clinically unimportant impact on the exposure of morphine after intravenous administration. Our results do not support pre‐emptive genotyping for OCT1 prior to morphine administration in patients scheduled for major surgery. |
| doi_str_mv | 10.1111/bcpt.13667 |
| format | Article |
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Eighty‐six patients completed the trial. The mean difference (95% confidence interval) for dose adjusted morphine, M3G and M6G AUC was 0.9 (−0.7–2.4), −5.9 (−11.8 to −0.03) and −1.1 (−2.5–0.4) h/L*10−6, respectively, in patients with two reduced function alleles compared to patients with no reduced function alleles in OCT1. Accordingly, the (AUCM3G/Dose)/(AUCmorphine/Dose) and (AUCM6G/Dose)/(AUCmorphine/Dose) ratio was reduced, −1.8 (−3.2 to −0.4) and −0.4 (−0.7 to −0.03), respectively, when comparing the same groups. OCT1 variants had no influence on the experience of pain, adverse events or the number of PCA doses used. In conclusion, genetic variants in OCT1 had a small and clinically unimportant impact on the exposure of morphine after intravenous administration. Our results do not support pre‐emptive genotyping for OCT1 prior to morphine administration in patients scheduled for major surgery.</description><identifier>ISSN: 1742-7835</identifier><identifier>ISSN: 1742-7843</identifier><identifier>EISSN: 1742-7843</identifier><identifier>DOI: 10.1111/bcpt.13667</identifier><identifier>PMID: 34599645</identifier><language>eng</language><publisher>England: Wiley Subscription Services, Inc</publisher><subject>Aged ; Alleles ; Analgesics, Opioid - administration & dosage ; Analgesics, Opioid - pharmacokinetics ; Area Under Curve ; Clinical Pharmacology ; Confidence intervals ; Female ; Genetic diversity ; Genetic variance ; Genetic Variation ; Genotype ; Genotypes ; Genotyping ; Humans ; Intravenous administration ; M6G ; Male ; Middle Aged ; Morphine ; Morphine - administration & dosage ; Morphine - pharmacokinetics ; Morphine Derivatives - pharmacokinetics ; Octamer Transcription Factor-1 - genetics ; organic cation transporter 1 ; Original ; Pain ; Pain, Postoperative - drug therapy ; Patients ; pharmacodynamics ; Pharmacokinetics ; Pharmacology ; Surgery ; Time Factors</subject><ispartof>Basic & clinical pharmacology & toxicology, 2022-01, Vol.130 (1), p.93-102</ispartof><rights>2021 The Authors. published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).</rights><rights>2021 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).</rights><rights>2021. This article is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4487-c4cad45cb69648ffad09fea62d3ed7e1bccb7473c7270d02bb75c4bdf9fc16483</citedby><cites>FETCH-LOGICAL-c4487-c4cad45cb69648ffad09fea62d3ed7e1bccb7473c7270d02bb75c4bdf9fc16483</cites><orcidid>0000-0003-0591-7187 ; 0000-0001-8444-7835 ; 0000-0003-1727-1264 ; 0000-0001-8313-0721 ; 0000-0002-4698-4389</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fbcpt.13667$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fbcpt.13667$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,315,782,786,887,1419,27931,27932,45581,45582</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34599645$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kuhlmann, Ida</creatorcontrib><creatorcontrib>Hjelmar Petersen, Rasmus</creatorcontrib><creatorcontrib>Overgaard, Morten</creatorcontrib><creatorcontrib>Dornonville de la Cour, Kenn</creatorcontrib><creatorcontrib>Zwisler, Stine</creatorcontrib><creatorcontrib>Bjerregaard Stage, Tore</creatorcontrib><creatorcontrib>Hougaard Christensen, Mette Marie</creatorcontrib><creatorcontrib>Bergmann, Troels K.</creatorcontrib><creatorcontrib>Damkier, Per</creatorcontrib><creatorcontrib>Gadegaard Jensen, Anders</creatorcontrib><creatorcontrib>Nielsen, Flemming</creatorcontrib><creatorcontrib>Brøsen, Kim</creatorcontrib><title>No significant influence of OCT1 genotypes on the pharmacokinetics of morphine in adult surgical patients</title><title>Basic & clinical pharmacology & toxicology</title><addtitle>Basic Clin Pharmacol Toxicol</addtitle><description>We investigated the impact of genetic variants in OCT1 (SLC22A1) on morphine, morphine‐3‐glucuronide (M3G) and morphine‐6‐glucuronide (M6G) pharmacokinetics in adult patients scheduled for major surgery. Blood samples were taken before and 5, 10, 15, 30, 45, 60 and 90 min after a bolus of morphine (0.15 mg/kg). Patients were genotyped for the genetic variants (rs12208357, rs34059508, rs72552763 and rs34130495) in OCT1.
Eighty‐six patients completed the trial. The mean difference (95% confidence interval) for dose adjusted morphine, M3G and M6G AUC was 0.9 (−0.7–2.4), −5.9 (−11.8 to −0.03) and −1.1 (−2.5–0.4) h/L*10−6, respectively, in patients with two reduced function alleles compared to patients with no reduced function alleles in OCT1. Accordingly, the (AUCM3G/Dose)/(AUCmorphine/Dose) and (AUCM6G/Dose)/(AUCmorphine/Dose) ratio was reduced, −1.8 (−3.2 to −0.4) and −0.4 (−0.7 to −0.03), respectively, when comparing the same groups. OCT1 variants had no influence on the experience of pain, adverse events or the number of PCA doses used. In conclusion, genetic variants in OCT1 had a small and clinically unimportant impact on the exposure of morphine after intravenous administration. Our results do not support pre‐emptive genotyping for OCT1 prior to morphine administration in patients scheduled for major surgery.</description><subject>Aged</subject><subject>Alleles</subject><subject>Analgesics, Opioid - administration & dosage</subject><subject>Analgesics, Opioid - pharmacokinetics</subject><subject>Area Under Curve</subject><subject>Clinical Pharmacology</subject><subject>Confidence intervals</subject><subject>Female</subject><subject>Genetic diversity</subject><subject>Genetic variance</subject><subject>Genetic Variation</subject><subject>Genotype</subject><subject>Genotypes</subject><subject>Genotyping</subject><subject>Humans</subject><subject>Intravenous administration</subject><subject>M6G</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Morphine</subject><subject>Morphine - administration & dosage</subject><subject>Morphine - pharmacokinetics</subject><subject>Morphine Derivatives - pharmacokinetics</subject><subject>Octamer Transcription Factor-1 - genetics</subject><subject>organic cation transporter 1</subject><subject>Original</subject><subject>Pain</subject><subject>Pain, Postoperative - drug therapy</subject><subject>Patients</subject><subject>pharmacodynamics</subject><subject>Pharmacokinetics</subject><subject>Pharmacology</subject><subject>Surgery</subject><subject>Time Factors</subject><issn>1742-7835</issn><issn>1742-7843</issn><issn>1742-7843</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp9kUtP3DAURi3UCihlww-oLHVTIQ3Ej8TJphIdUaiEoIthbTnO9YxpYgfbaTX_Hg8Do9JFvfBDPvf4Wh9CJ6Q4I3mct3pMZ4RVldhDh0RwOhM1Z-92e1YeoA8xPhQFFZwU--iA8bJpKl4eInvrcbRLZ43VyiVsnekncBqwN_huviB4Cc6n9QgRe4fTCvC4UmFQ2v-yDpLVcUMOPoyrfM71WHVTn3CcwjIrezyqZMGl-BG9N6qPcPyyHqH775eL-fXs5u7qx_ziZqY5r0Wetep4qdsqN1gbo7qiMaAq2jHoBJBW61ZwwbSgougK2rai1LztTGM0yRXsCH3desepHaDT-e2gejkGO6iwll5Z-fbG2ZVc-t-yoU3N2Ebw5UUQ_OMEMcnBRg19rxz4KUpailpUjAmR0c__oA9-Ci5_T9KK1JSUgrBMnW4pHXyMAcyuGVLITYJyk6B8TjDDn_5uf4e-RpYBsgX-2B7W_1HJb_Ofi630CVavqV4</recordid><startdate>202201</startdate><enddate>202201</enddate><creator>Kuhlmann, Ida</creator><creator>Hjelmar Petersen, Rasmus</creator><creator>Overgaard, Morten</creator><creator>Dornonville de la Cour, Kenn</creator><creator>Zwisler, Stine</creator><creator>Bjerregaard Stage, Tore</creator><creator>Hougaard Christensen, Mette Marie</creator><creator>Bergmann, Troels K.</creator><creator>Damkier, Per</creator><creator>Gadegaard Jensen, Anders</creator><creator>Nielsen, Flemming</creator><creator>Brøsen, Kim</creator><general>Wiley Subscription Services, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</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>7QP</scope><scope>7TK</scope><scope>7U7</scope><scope>C1K</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-0591-7187</orcidid><orcidid>https://orcid.org/0000-0001-8444-7835</orcidid><orcidid>https://orcid.org/0000-0003-1727-1264</orcidid><orcidid>https://orcid.org/0000-0001-8313-0721</orcidid><orcidid>https://orcid.org/0000-0002-4698-4389</orcidid></search><sort><creationdate>202201</creationdate><title>No significant influence of OCT1 genotypes on the pharmacokinetics of morphine in adult surgical patients</title><author>Kuhlmann, Ida ; Hjelmar Petersen, Rasmus ; Overgaard, Morten ; Dornonville de la Cour, Kenn ; Zwisler, Stine ; Bjerregaard Stage, Tore ; Hougaard Christensen, Mette Marie ; Bergmann, Troels K. ; Damkier, Per ; Gadegaard Jensen, Anders ; Nielsen, Flemming ; Brøsen, Kim</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4487-c4cad45cb69648ffad09fea62d3ed7e1bccb7473c7270d02bb75c4bdf9fc16483</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Aged</topic><topic>Alleles</topic><topic>Analgesics, Opioid - administration & dosage</topic><topic>Analgesics, Opioid - pharmacokinetics</topic><topic>Area Under Curve</topic><topic>Clinical Pharmacology</topic><topic>Confidence intervals</topic><topic>Female</topic><topic>Genetic diversity</topic><topic>Genetic variance</topic><topic>Genetic Variation</topic><topic>Genotype</topic><topic>Genotypes</topic><topic>Genotyping</topic><topic>Humans</topic><topic>Intravenous administration</topic><topic>M6G</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Morphine</topic><topic>Morphine - administration & dosage</topic><topic>Morphine - pharmacokinetics</topic><topic>Morphine Derivatives - pharmacokinetics</topic><topic>Octamer Transcription Factor-1 - genetics</topic><topic>organic cation transporter 1</topic><topic>Original</topic><topic>Pain</topic><topic>Pain, Postoperative - drug therapy</topic><topic>Patients</topic><topic>pharmacodynamics</topic><topic>Pharmacokinetics</topic><topic>Pharmacology</topic><topic>Surgery</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kuhlmann, Ida</creatorcontrib><creatorcontrib>Hjelmar Petersen, Rasmus</creatorcontrib><creatorcontrib>Overgaard, Morten</creatorcontrib><creatorcontrib>Dornonville de la Cour, Kenn</creatorcontrib><creatorcontrib>Zwisler, Stine</creatorcontrib><creatorcontrib>Bjerregaard Stage, Tore</creatorcontrib><creatorcontrib>Hougaard Christensen, Mette Marie</creatorcontrib><creatorcontrib>Bergmann, Troels K.</creatorcontrib><creatorcontrib>Damkier, Per</creatorcontrib><creatorcontrib>Gadegaard Jensen, Anders</creatorcontrib><creatorcontrib>Nielsen, Flemming</creatorcontrib><creatorcontrib>Brøsen, Kim</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library (Open Access Collection)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Basic & clinical pharmacology & toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kuhlmann, Ida</au><au>Hjelmar Petersen, Rasmus</au><au>Overgaard, Morten</au><au>Dornonville de la Cour, Kenn</au><au>Zwisler, Stine</au><au>Bjerregaard Stage, Tore</au><au>Hougaard Christensen, Mette Marie</au><au>Bergmann, Troels K.</au><au>Damkier, Per</au><au>Gadegaard Jensen, Anders</au><au>Nielsen, Flemming</au><au>Brøsen, Kim</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>No significant influence of OCT1 genotypes on the pharmacokinetics of morphine in adult surgical patients</atitle><jtitle>Basic & clinical pharmacology & toxicology</jtitle><addtitle>Basic Clin Pharmacol Toxicol</addtitle><date>2022-01</date><risdate>2022</risdate><volume>130</volume><issue>1</issue><spage>93</spage><epage>102</epage><pages>93-102</pages><issn>1742-7835</issn><issn>1742-7843</issn><eissn>1742-7843</eissn><abstract>We investigated the impact of genetic variants in OCT1 (SLC22A1) on morphine, morphine‐3‐glucuronide (M3G) and morphine‐6‐glucuronide (M6G) pharmacokinetics in adult patients scheduled for major surgery. Blood samples were taken before and 5, 10, 15, 30, 45, 60 and 90 min after a bolus of morphine (0.15 mg/kg). Patients were genotyped for the genetic variants (rs12208357, rs34059508, rs72552763 and rs34130495) in OCT1.
Eighty‐six patients completed the trial. The mean difference (95% confidence interval) for dose adjusted morphine, M3G and M6G AUC was 0.9 (−0.7–2.4), −5.9 (−11.8 to −0.03) and −1.1 (−2.5–0.4) h/L*10−6, respectively, in patients with two reduced function alleles compared to patients with no reduced function alleles in OCT1. Accordingly, the (AUCM3G/Dose)/(AUCmorphine/Dose) and (AUCM6G/Dose)/(AUCmorphine/Dose) ratio was reduced, −1.8 (−3.2 to −0.4) and −0.4 (−0.7 to −0.03), respectively, when comparing the same groups. OCT1 variants had no influence on the experience of pain, adverse events or the number of PCA doses used. In conclusion, genetic variants in OCT1 had a small and clinically unimportant impact on the exposure of morphine after intravenous administration. Our results do not support pre‐emptive genotyping for OCT1 prior to morphine administration in patients scheduled for major surgery.</abstract><cop>England</cop><pub>Wiley Subscription Services, Inc</pub><pmid>34599645</pmid><doi>10.1111/bcpt.13667</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0003-0591-7187</orcidid><orcidid>https://orcid.org/0000-0001-8444-7835</orcidid><orcidid>https://orcid.org/0000-0003-1727-1264</orcidid><orcidid>https://orcid.org/0000-0001-8313-0721</orcidid><orcidid>https://orcid.org/0000-0002-4698-4389</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Aged Alleles Analgesics, Opioid - administration & dosage Analgesics, Opioid - pharmacokinetics Area Under Curve Clinical Pharmacology Confidence intervals Female Genetic diversity Genetic variance Genetic Variation Genotype Genotypes Genotyping Humans Intravenous administration M6G Male Middle Aged Morphine Morphine - administration & dosage Morphine - pharmacokinetics Morphine Derivatives - pharmacokinetics Octamer Transcription Factor-1 - genetics organic cation transporter 1 Original Pain Pain, Postoperative - drug therapy Patients pharmacodynamics Pharmacokinetics Pharmacology Surgery Time Factors |
| title | No significant influence of OCT1 genotypes on the pharmacokinetics of morphine in adult surgical patients |
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