Liver Cirrhosis Affects the Pharmacokinetics of the Six Substrates of the Basel Phenotyping Cocktail Differently
Activities of hepatic cytochrome P450 enzymes (CYPs) are relevant for hepatic clearance of drugs and known to be decreased in patients with liver cirrhosis. Several studies have reported the effect of liver cirrhosis on CYP activity, but the results are partially conflicting and for some CYPs lackin...
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| Veröffentlicht in: | Clinical pharmacokinetics 2022-07, Vol.61 (7), p.1039-1055 |
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| creator | Duthaler, Urs Bachmann, Fabio Suenderhauf, Claudia Grandinetti, Tanja Pfefferkorn, Florian Haschke, Manuel Hruz, Petr Bouitbir, Jamal Krähenbühl, Stephan |
| description | Activities of hepatic cytochrome P450 enzymes (CYPs) are relevant for hepatic clearance of drugs and known to be decreased in patients with liver cirrhosis. Several studies have reported the effect of liver cirrhosis on CYP activity, but the results are partially conflicting and for some CYPs lacking.
In this study, we aimed to investigate the CYP activity in patients with liver cirrhosis with different Child stages (A-C) using the Basel phenotyping cocktail approach.
We assessed the pharmacokinetics of the six compounds and their CYP-specific metabolites of the Basel phenotyping cocktail (CYP1A2: caffeine, CYP2B6: efavirenz, CYP2C9: flurbiprofen, CYP2C19: omeprazole, CYP2D6: metoprolol, CYP3A: midazolam) in patients with liver cirrhosis (n = 16 Child A cirrhosis, n = 15 Child B cirrhosis, n = 5 Child C cirrhosis) and matched control subjects (n = 12).
While liver cirrhosis only marginally affected the pharmacokinetics of the low to moderate extraction drugs efavirenz and flurbiprofen, the elimination rate of caffeine was reduced by 51% in patients with Child C cirrhosis. For the moderate to high extraction drugs omeprazole, metoprolol, and midazolam, liver cirrhosis decreased the elimination rate by 75%, 37%, and 60%, respectively, increased exposure, and decreased the apparent systemic clearance (clearance/bioavailability). In patients with Child C cirrhosis, the metabolic ratio (ratio of the area under the plasma concentration-time curve from 0 to 24 h of the metabolite to the parent compound), a marker for CYP activity, decreased by 66%, 47%, 92%, 73%, and 43% for paraxanthine/caffeine (CYP1A2), 8-hydroxyefavirenz/efavirenz (CYP2B6), 5-hydroxyomeprazole/omeprazole (CYP2C19), α-hydroxymetoprolol/metoprolol (CYP2D6), and 1'-hydroxymidazolam/midazolam (CYP3A), respectively. In comparison, the metabolic ratio 4-hydroxyflurbiprofen/flurbiprofen (CYP2C9) remained unchanged.
Liver cirrhosis affects the activity of CYP isoforms differently. This variability must be considered for dose adjustment of drugs in patients with liver cirrhosis.
NCT03337945. |
| doi_str_mv | 10.1007/s40262-022-01119-0 |
| format | Article |
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In this study, we aimed to investigate the CYP activity in patients with liver cirrhosis with different Child stages (A-C) using the Basel phenotyping cocktail approach.
We assessed the pharmacokinetics of the six compounds and their CYP-specific metabolites of the Basel phenotyping cocktail (CYP1A2: caffeine, CYP2B6: efavirenz, CYP2C9: flurbiprofen, CYP2C19: omeprazole, CYP2D6: metoprolol, CYP3A: midazolam) in patients with liver cirrhosis (n = 16 Child A cirrhosis, n = 15 Child B cirrhosis, n = 5 Child C cirrhosis) and matched control subjects (n = 12).
While liver cirrhosis only marginally affected the pharmacokinetics of the low to moderate extraction drugs efavirenz and flurbiprofen, the elimination rate of caffeine was reduced by 51% in patients with Child C cirrhosis. For the moderate to high extraction drugs omeprazole, metoprolol, and midazolam, liver cirrhosis decreased the elimination rate by 75%, 37%, and 60%, respectively, increased exposure, and decreased the apparent systemic clearance (clearance/bioavailability). In patients with Child C cirrhosis, the metabolic ratio (ratio of the area under the plasma concentration-time curve from 0 to 24 h of the metabolite to the parent compound), a marker for CYP activity, decreased by 66%, 47%, 92%, 73%, and 43% for paraxanthine/caffeine (CYP1A2), 8-hydroxyefavirenz/efavirenz (CYP2B6), 5-hydroxyomeprazole/omeprazole (CYP2C19), α-hydroxymetoprolol/metoprolol (CYP2D6), and 1'-hydroxymidazolam/midazolam (CYP3A), respectively. In comparison, the metabolic ratio 4-hydroxyflurbiprofen/flurbiprofen (CYP2C9) remained unchanged.
Liver cirrhosis affects the activity of CYP isoforms differently. This variability must be considered for dose adjustment of drugs in patients with liver cirrhosis.
NCT03337945.</description><identifier>ISSN: 0312-5963</identifier><identifier>ISSN: 1179-1926</identifier><identifier>EISSN: 1179-1926</identifier><identifier>DOI: 10.1007/s40262-022-01119-0</identifier><identifier>PMID: 35570253</identifier><language>eng</language><publisher>Switzerland: Springer Nature B.V</publisher><subject>Bioavailability ; Caffeine ; Caffeine - pharmacokinetics ; Child ; Cytochrome ; Cytochrome P-450 CYP1A2 - metabolism ; Cytochrome P-450 CYP2B6 ; Cytochrome P-450 CYP2C19 ; Cytochrome P-450 CYP2C9 ; Cytochrome P-450 CYP2D6 - metabolism ; Cytochrome P-450 CYP3A - metabolism ; Cytochrome P-450 Enzyme System - metabolism ; Drug dosages ; Enzymes ; Flurbiprofen - pharmacokinetics ; Humans ; Liver Cirrhosis ; Liver diseases ; Metabolism ; Metabolites ; Metoprolol ; Midazolam - pharmacokinetics ; Omeprazole ; Original ; Pharmacokinetics ; Plasma</subject><ispartof>Clinical pharmacokinetics, 2022-07, Vol.61 (7), p.1039-1055</ispartof><rights>2022. The Author(s).</rights><rights>Copyright Springer Nature B.V. Jul 2022</rights><rights>The Author(s) 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3450-fe45adbcd56534ce6b3171ba9f837f4a9b3aeebe419469db9e9ac70f957974033</citedby><cites>FETCH-LOGICAL-c3450-fe45adbcd56534ce6b3171ba9f837f4a9b3aeebe419469db9e9ac70f957974033</cites><orcidid>0000-0002-4246-6824</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35570253$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Duthaler, Urs</creatorcontrib><creatorcontrib>Bachmann, Fabio</creatorcontrib><creatorcontrib>Suenderhauf, Claudia</creatorcontrib><creatorcontrib>Grandinetti, Tanja</creatorcontrib><creatorcontrib>Pfefferkorn, Florian</creatorcontrib><creatorcontrib>Haschke, Manuel</creatorcontrib><creatorcontrib>Hruz, Petr</creatorcontrib><creatorcontrib>Bouitbir, Jamal</creatorcontrib><creatorcontrib>Krähenbühl, Stephan</creatorcontrib><title>Liver Cirrhosis Affects the Pharmacokinetics of the Six Substrates of the Basel Phenotyping Cocktail Differently</title><title>Clinical pharmacokinetics</title><addtitle>Clin Pharmacokinet</addtitle><description>Activities of hepatic cytochrome P450 enzymes (CYPs) are relevant for hepatic clearance of drugs and known to be decreased in patients with liver cirrhosis. Several studies have reported the effect of liver cirrhosis on CYP activity, but the results are partially conflicting and for some CYPs lacking.
In this study, we aimed to investigate the CYP activity in patients with liver cirrhosis with different Child stages (A-C) using the Basel phenotyping cocktail approach.
We assessed the pharmacokinetics of the six compounds and their CYP-specific metabolites of the Basel phenotyping cocktail (CYP1A2: caffeine, CYP2B6: efavirenz, CYP2C9: flurbiprofen, CYP2C19: omeprazole, CYP2D6: metoprolol, CYP3A: midazolam) in patients with liver cirrhosis (n = 16 Child A cirrhosis, n = 15 Child B cirrhosis, n = 5 Child C cirrhosis) and matched control subjects (n = 12).
While liver cirrhosis only marginally affected the pharmacokinetics of the low to moderate extraction drugs efavirenz and flurbiprofen, the elimination rate of caffeine was reduced by 51% in patients with Child C cirrhosis. For the moderate to high extraction drugs omeprazole, metoprolol, and midazolam, liver cirrhosis decreased the elimination rate by 75%, 37%, and 60%, respectively, increased exposure, and decreased the apparent systemic clearance (clearance/bioavailability). In patients with Child C cirrhosis, the metabolic ratio (ratio of the area under the plasma concentration-time curve from 0 to 24 h of the metabolite to the parent compound), a marker for CYP activity, decreased by 66%, 47%, 92%, 73%, and 43% for paraxanthine/caffeine (CYP1A2), 8-hydroxyefavirenz/efavirenz (CYP2B6), 5-hydroxyomeprazole/omeprazole (CYP2C19), α-hydroxymetoprolol/metoprolol (CYP2D6), and 1'-hydroxymidazolam/midazolam (CYP3A), respectively. In comparison, the metabolic ratio 4-hydroxyflurbiprofen/flurbiprofen (CYP2C9) remained unchanged.
Liver cirrhosis affects the activity of CYP isoforms differently. This variability must be considered for dose adjustment of drugs in patients with liver cirrhosis.
NCT03337945.</description><subject>Bioavailability</subject><subject>Caffeine</subject><subject>Caffeine - pharmacokinetics</subject><subject>Child</subject><subject>Cytochrome</subject><subject>Cytochrome P-450 CYP1A2 - metabolism</subject><subject>Cytochrome P-450 CYP2B6</subject><subject>Cytochrome P-450 CYP2C19</subject><subject>Cytochrome P-450 CYP2C9</subject><subject>Cytochrome P-450 CYP2D6 - metabolism</subject><subject>Cytochrome P-450 CYP3A - metabolism</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Drug dosages</subject><subject>Enzymes</subject><subject>Flurbiprofen - pharmacokinetics</subject><subject>Humans</subject><subject>Liver Cirrhosis</subject><subject>Liver diseases</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Metoprolol</subject><subject>Midazolam - pharmacokinetics</subject><subject>Omeprazole</subject><subject>Original</subject><subject>Pharmacokinetics</subject><subject>Plasma</subject><issn>0312-5963</issn><issn>1179-1926</issn><issn>1179-1926</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNpdkc9uEzEQhy0EomnhBTiglbhwWRj_W8cXpDYtUCkSlQpny-uMu24369Tercjb9Fl4MkzTRsDBsjT-5jcefYS8ofCBAqiPWQBrWA2sHEqpruEZmVGqdE01a56TGXDKaqkbfkAOc74GgDkDeEkOuJQKmOQzcrsMd5iqRUipiznk6th7dGOuxg6ri86mtXXxJgw4Bper6B_ql-FndTm1eUx2xH31xGbsf91fdDjEcbsJw1W1iO5mtKGvTkOJTTiM_fYVeeFtn_H1431Efnw--774Wi-_fTlfHC9rx4WE2qOQdtW6lWwkFw6bllNFW6v9nCsvrG65RWxRUC0avWo1ausUeC2VVgI4PyKfdrmbqV3jypXhyfZmk8Lapq2JNph_X4bQmat4ZzSbK8ZECXj_GJDi7YR5NOuQHfa9HTBO2bCmkRSUYKyg7_5Dr-OUhrJeoTSlwLimhWI7yqWYc0K__wwF88eo2Rk1xah5MGqgNL39e419y5NC_hu8ZJ7Z</recordid><startdate>20220701</startdate><enddate>20220701</enddate><creator>Duthaler, Urs</creator><creator>Bachmann, Fabio</creator><creator>Suenderhauf, Claudia</creator><creator>Grandinetti, Tanja</creator><creator>Pfefferkorn, Florian</creator><creator>Haschke, Manuel</creator><creator>Hruz, Petr</creator><creator>Bouitbir, Jamal</creator><creator>Krähenbühl, Stephan</creator><general>Springer Nature B.V</general><general>Springer International Publishing</general><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>3V.</scope><scope>4T-</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-4246-6824</orcidid></search><sort><creationdate>20220701</creationdate><title>Liver Cirrhosis Affects the Pharmacokinetics of the Six Substrates of the Basel Phenotyping Cocktail Differently</title><author>Duthaler, Urs ; Bachmann, Fabio ; Suenderhauf, Claudia ; Grandinetti, Tanja ; Pfefferkorn, Florian ; Haschke, Manuel ; Hruz, Petr ; Bouitbir, Jamal ; Krähenbühl, Stephan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3450-fe45adbcd56534ce6b3171ba9f837f4a9b3aeebe419469db9e9ac70f957974033</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Bioavailability</topic><topic>Caffeine</topic><topic>Caffeine - pharmacokinetics</topic><topic>Child</topic><topic>Cytochrome</topic><topic>Cytochrome P-450 CYP1A2 - metabolism</topic><topic>Cytochrome P-450 CYP2B6</topic><topic>Cytochrome P-450 CYP2C19</topic><topic>Cytochrome P-450 CYP2C9</topic><topic>Cytochrome P-450 CYP2D6 - metabolism</topic><topic>Cytochrome P-450 CYP3A - metabolism</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>Drug dosages</topic><topic>Enzymes</topic><topic>Flurbiprofen - pharmacokinetics</topic><topic>Humans</topic><topic>Liver Cirrhosis</topic><topic>Liver diseases</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Metoprolol</topic><topic>Midazolam - pharmacokinetics</topic><topic>Omeprazole</topic><topic>Original</topic><topic>Pharmacokinetics</topic><topic>Plasma</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Duthaler, Urs</creatorcontrib><creatorcontrib>Bachmann, Fabio</creatorcontrib><creatorcontrib>Suenderhauf, Claudia</creatorcontrib><creatorcontrib>Grandinetti, Tanja</creatorcontrib><creatorcontrib>Pfefferkorn, Florian</creatorcontrib><creatorcontrib>Haschke, Manuel</creatorcontrib><creatorcontrib>Hruz, Petr</creatorcontrib><creatorcontrib>Bouitbir, Jamal</creatorcontrib><creatorcontrib>Krähenbühl, Stephan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Docstoc</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Clinical pharmacokinetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Duthaler, Urs</au><au>Bachmann, Fabio</au><au>Suenderhauf, Claudia</au><au>Grandinetti, Tanja</au><au>Pfefferkorn, Florian</au><au>Haschke, Manuel</au><au>Hruz, Petr</au><au>Bouitbir, Jamal</au><au>Krähenbühl, Stephan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Liver Cirrhosis Affects the Pharmacokinetics of the Six Substrates of the Basel Phenotyping Cocktail Differently</atitle><jtitle>Clinical pharmacokinetics</jtitle><addtitle>Clin Pharmacokinet</addtitle><date>2022-07-01</date><risdate>2022</risdate><volume>61</volume><issue>7</issue><spage>1039</spage><epage>1055</epage><pages>1039-1055</pages><issn>0312-5963</issn><issn>1179-1926</issn><eissn>1179-1926</eissn><abstract>Activities of hepatic cytochrome P450 enzymes (CYPs) are relevant for hepatic clearance of drugs and known to be decreased in patients with liver cirrhosis. Several studies have reported the effect of liver cirrhosis on CYP activity, but the results are partially conflicting and for some CYPs lacking.
In this study, we aimed to investigate the CYP activity in patients with liver cirrhosis with different Child stages (A-C) using the Basel phenotyping cocktail approach.
We assessed the pharmacokinetics of the six compounds and their CYP-specific metabolites of the Basel phenotyping cocktail (CYP1A2: caffeine, CYP2B6: efavirenz, CYP2C9: flurbiprofen, CYP2C19: omeprazole, CYP2D6: metoprolol, CYP3A: midazolam) in patients with liver cirrhosis (n = 16 Child A cirrhosis, n = 15 Child B cirrhosis, n = 5 Child C cirrhosis) and matched control subjects (n = 12).
While liver cirrhosis only marginally affected the pharmacokinetics of the low to moderate extraction drugs efavirenz and flurbiprofen, the elimination rate of caffeine was reduced by 51% in patients with Child C cirrhosis. For the moderate to high extraction drugs omeprazole, metoprolol, and midazolam, liver cirrhosis decreased the elimination rate by 75%, 37%, and 60%, respectively, increased exposure, and decreased the apparent systemic clearance (clearance/bioavailability). In patients with Child C cirrhosis, the metabolic ratio (ratio of the area under the plasma concentration-time curve from 0 to 24 h of the metabolite to the parent compound), a marker for CYP activity, decreased by 66%, 47%, 92%, 73%, and 43% for paraxanthine/caffeine (CYP1A2), 8-hydroxyefavirenz/efavirenz (CYP2B6), 5-hydroxyomeprazole/omeprazole (CYP2C19), α-hydroxymetoprolol/metoprolol (CYP2D6), and 1'-hydroxymidazolam/midazolam (CYP3A), respectively. In comparison, the metabolic ratio 4-hydroxyflurbiprofen/flurbiprofen (CYP2C9) remained unchanged.
Liver cirrhosis affects the activity of CYP isoforms differently. This variability must be considered for dose adjustment of drugs in patients with liver cirrhosis.
NCT03337945.</abstract><cop>Switzerland</cop><pub>Springer Nature B.V</pub><pmid>35570253</pmid><doi>10.1007/s40262-022-01119-0</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0002-4246-6824</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Clinical pharmacokinetics, 2022-07, Vol.61 (7), p.1039-1055 |
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| source | MEDLINE; SpringerNature Journals |
| subjects | Bioavailability Caffeine Caffeine - pharmacokinetics Child Cytochrome Cytochrome P-450 CYP1A2 - metabolism Cytochrome P-450 CYP2B6 Cytochrome P-450 CYP2C19 Cytochrome P-450 CYP2C9 Cytochrome P-450 CYP2D6 - metabolism Cytochrome P-450 CYP3A - metabolism Cytochrome P-450 Enzyme System - metabolism Drug dosages Enzymes Flurbiprofen - pharmacokinetics Humans Liver Cirrhosis Liver diseases Metabolism Metabolites Metoprolol Midazolam - pharmacokinetics Omeprazole Original Pharmacokinetics Plasma |
| title | Liver Cirrhosis Affects the Pharmacokinetics of the Six Substrates of the Basel Phenotyping Cocktail Differently |
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