Pharmacokinetic interaction of intravenous fentanyl with ketoconazole
Fentanyl is primarily metabolized by CYP3A, but has also been suggested to act as a weak inhibitor of CYP3A. We investigated the influence of CYP3A inhibition by ketoconazole on the pharmacokinetics of intravenously administered fentanyl and the effect of fentanyl on CYP3A activity. A prospective, o...
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| Veröffentlicht in: | Journal of clinical pharmacology 2015-06, Vol.55 (6), p.708-717 |
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| creator | Ziesenitz, Victoria C. König, Sonja K. Mahlke, Nina S. Skopp, Gisela Haefeli, Walter E. Mikus, Gerd |
| description | Fentanyl is primarily metabolized by CYP3A, but has also been suggested to act as a weak inhibitor of CYP3A. We investigated the influence of CYP3A inhibition by ketoconazole on the pharmacokinetics of intravenously administered fentanyl and the effect of fentanyl on CYP3A activity. A prospective, open‐label, randomized, monocentre, crossover study was conducted in 16 healthy volunteers. They received fentanyl alone (5 microgram per kilogram) or fentanyl plus ketoconazole (200 milligram orally B.I.D. over 2 days). Naloxone (2 × 0.2 milligram i.v.) was given simultaneously with fentanyl to mitigate any opioid effect. Midazolam was administered as a CYP3A probe drug. Fentanyl and its metabolites were quantified by LC/MS/MS in blood and urine samples obtained over 24 hour. Exposure of fentanyl (AUC0‐∞) was significantly increased to 133% and systemic clearance was reduced to 78% by ketoconazole, norfentanyl formation was significantly delayed and partial metabolic clearance decreased to 18%. Fentanyl had no influence on midazolam exposure and CYP3A activity whereas ketoconazole decreased CYP3A activity to 13%. Although fentanyl N‐dealkylation is substantially inhibited by ketoconazole, exposure of fentanyl itself increased by one third only. Clinically fentanyl dosage adjustments may become necessary when ketoconazole or other strong CYP3A inhibitors are given simultaneously. Fentanyl itself does not influence CYP3A activity. |
| doi_str_mv | 10.1002/jcph.469 |
| format | Article |
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We investigated the influence of CYP3A inhibition by ketoconazole on the pharmacokinetics of intravenously administered fentanyl and the effect of fentanyl on CYP3A activity. A prospective, open‐label, randomized, monocentre, crossover study was conducted in 16 healthy volunteers. They received fentanyl alone (5 microgram per kilogram) or fentanyl plus ketoconazole (200 milligram orally B.I.D. over 2 days). Naloxone (2 × 0.2 milligram i.v.) was given simultaneously with fentanyl to mitigate any opioid effect. Midazolam was administered as a CYP3A probe drug. Fentanyl and its metabolites were quantified by LC/MS/MS in blood and urine samples obtained over 24 hour. Exposure of fentanyl (AUC0‐∞) was significantly increased to 133% and systemic clearance was reduced to 78% by ketoconazole, norfentanyl formation was significantly delayed and partial metabolic clearance decreased to 18%. Fentanyl had no influence on midazolam exposure and CYP3A activity whereas ketoconazole decreased CYP3A activity to 13%. Although fentanyl N‐dealkylation is substantially inhibited by ketoconazole, exposure of fentanyl itself increased by one third only. Clinically fentanyl dosage adjustments may become necessary when ketoconazole or other strong CYP3A inhibitors are given simultaneously. Fentanyl itself does not influence CYP3A activity.</description><identifier>ISSN: 0091-2700</identifier><identifier>EISSN: 1552-4604</identifier><identifier>DOI: 10.1002/jcph.469</identifier><identifier>PMID: 25651378</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject><![CDATA[Administration, Intravenous ; Adult ; Analgesics, Opioid - administration & dosage ; Analgesics, Opioid - pharmacokinetics ; Chromatography, Liquid ; Cross-Over Studies ; CYP3A inhibition ; Cytochrome P-450 CYP3A - blood ; Cytochrome P-450 CYP3A - metabolism ; Cytochrome P-450 CYP3A - urine ; Cytochrome P-450 CYP3A Inhibitors - administration & dosage ; Cytochrome P-450 CYP3A Inhibitors - pharmacokinetics ; Drug Interactions ; Female ; fentanyl ; Fentanyl - administration & dosage ; Fentanyl - analogs & derivatives ; Fentanyl - blood ; Fentanyl - metabolism ; Fentanyl - pharmacokinetics ; Fentanyl - urine ; Healthy Volunteers ; Humans ; ketoconazole ; Ketoconazole - administration & dosage ; Ketoconazole - pharmacokinetics ; Male ; Midazolam - administration & dosage ; Middle Aged ; Naloxone - administration & dosage ; Prospective Studies ; Tandem Mass Spectrometry ; Young Adult]]></subject><ispartof>Journal of clinical pharmacology, 2015-06, Vol.55 (6), p.708-717</ispartof><rights>2015, The American College of Clinical Pharmacology</rights><rights>2015 American College of Clinical Pharmacology</rights><rights>2015, The American College of Clinical Pharmacology.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4839-e21be08d9824dedfb498e58ea018fdd7a4fdae07e9e160b25b95381732c4bea73</citedby><cites>FETCH-LOGICAL-c4839-e21be08d9824dedfb498e58ea018fdd7a4fdae07e9e160b25b95381732c4bea73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjcph.469$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcph.469$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,782,786,1419,27933,27934,45583,45584</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25651378$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ziesenitz, Victoria C.</creatorcontrib><creatorcontrib>König, Sonja K.</creatorcontrib><creatorcontrib>Mahlke, Nina S.</creatorcontrib><creatorcontrib>Skopp, Gisela</creatorcontrib><creatorcontrib>Haefeli, Walter E.</creatorcontrib><creatorcontrib>Mikus, Gerd</creatorcontrib><title>Pharmacokinetic interaction of intravenous fentanyl with ketoconazole</title><title>Journal of clinical pharmacology</title><addtitle>The Journal of Clinical Pharmacology</addtitle><description>Fentanyl is primarily metabolized by CYP3A, but has also been suggested to act as a weak inhibitor of CYP3A. We investigated the influence of CYP3A inhibition by ketoconazole on the pharmacokinetics of intravenously administered fentanyl and the effect of fentanyl on CYP3A activity. A prospective, open‐label, randomized, monocentre, crossover study was conducted in 16 healthy volunteers. They received fentanyl alone (5 microgram per kilogram) or fentanyl plus ketoconazole (200 milligram orally B.I.D. over 2 days). Naloxone (2 × 0.2 milligram i.v.) was given simultaneously with fentanyl to mitigate any opioid effect. Midazolam was administered as a CYP3A probe drug. Fentanyl and its metabolites were quantified by LC/MS/MS in blood and urine samples obtained over 24 hour. Exposure of fentanyl (AUC0‐∞) was significantly increased to 133% and systemic clearance was reduced to 78% by ketoconazole, norfentanyl formation was significantly delayed and partial metabolic clearance decreased to 18%. Fentanyl had no influence on midazolam exposure and CYP3A activity whereas ketoconazole decreased CYP3A activity to 13%. Although fentanyl N‐dealkylation is substantially inhibited by ketoconazole, exposure of fentanyl itself increased by one third only. Clinically fentanyl dosage adjustments may become necessary when ketoconazole or other strong CYP3A inhibitors are given simultaneously. Fentanyl itself does not influence CYP3A activity.</description><subject>Administration, Intravenous</subject><subject>Adult</subject><subject>Analgesics, Opioid - administration & dosage</subject><subject>Analgesics, Opioid - pharmacokinetics</subject><subject>Chromatography, Liquid</subject><subject>Cross-Over Studies</subject><subject>CYP3A inhibition</subject><subject>Cytochrome P-450 CYP3A - blood</subject><subject>Cytochrome P-450 CYP3A - metabolism</subject><subject>Cytochrome P-450 CYP3A - urine</subject><subject>Cytochrome P-450 CYP3A Inhibitors - administration & dosage</subject><subject>Cytochrome P-450 CYP3A Inhibitors - pharmacokinetics</subject><subject>Drug Interactions</subject><subject>Female</subject><subject>fentanyl</subject><subject>Fentanyl - administration & dosage</subject><subject>Fentanyl - analogs & derivatives</subject><subject>Fentanyl - blood</subject><subject>Fentanyl - metabolism</subject><subject>Fentanyl - pharmacokinetics</subject><subject>Fentanyl - urine</subject><subject>Healthy Volunteers</subject><subject>Humans</subject><subject>ketoconazole</subject><subject>Ketoconazole - administration & dosage</subject><subject>Ketoconazole - pharmacokinetics</subject><subject>Male</subject><subject>Midazolam - administration & dosage</subject><subject>Middle Aged</subject><subject>Naloxone - administration & dosage</subject><subject>Prospective Studies</subject><subject>Tandem Mass Spectrometry</subject><subject>Young Adult</subject><issn>0091-2700</issn><issn>1552-4604</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kFFrFDEURoModlsFf4EM-OJDpyaZZJJ51KW2StGKuoovIZO5w2R3NlmTjOv6683StajoUwgczv04CD0i-IxgTJ8tzWY4Y3VzB80I57RkNWZ30QzjhpRUYHyEjmNcYkxqxsl9dER5zUkl5AydXw86rLXxK-sgWVNYlyBok6x3he_336C_gfNTLHpwSbvdWGxtGooVJG-80z_8CA_QvV6PER4e3hP08eX5h_llefX24tX8-VVpmKyaEihpAcuukZR10PUtayRwCRoT2Xed0KzvNGABDZAat5S3Da8kERU1rAUtqhP09Ma7Cf7rBDGptY0GxlE7yAsVqWVWUS6ajD75C136Kbi8ThEhOMd5xG9CE3yMAXq1CXatw04RrPZp1T6tymkz-vggnNo1dLfgr5YZOL0Btn7MDeNqnLYQ1AB6TMO_fOUBtyPs_ntXvZ5fX_7B25jg-y2vw0rVohJcfXpzoT4vXrx7v6gW6kv1E5S6olY</recordid><startdate>201506</startdate><enddate>201506</enddate><creator>Ziesenitz, Victoria C.</creator><creator>König, Sonja K.</creator><creator>Mahlke, Nina S.</creator><creator>Skopp, Gisela</creator><creator>Haefeli, Walter E.</creator><creator>Mikus, Gerd</creator><general>Blackwell Publishing Ltd</general><general>American College of Clinical Pharmacology</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</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>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201506</creationdate><title>Pharmacokinetic interaction of intravenous fentanyl with ketoconazole</title><author>Ziesenitz, Victoria C. ; König, Sonja K. ; Mahlke, Nina S. ; Skopp, Gisela ; Haefeli, Walter E. ; Mikus, Gerd</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4839-e21be08d9824dedfb498e58ea018fdd7a4fdae07e9e160b25b95381732c4bea73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Administration, Intravenous</topic><topic>Adult</topic><topic>Analgesics, Opioid - administration & dosage</topic><topic>Analgesics, Opioid - pharmacokinetics</topic><topic>Chromatography, Liquid</topic><topic>Cross-Over Studies</topic><topic>CYP3A inhibition</topic><topic>Cytochrome P-450 CYP3A - blood</topic><topic>Cytochrome P-450 CYP3A - metabolism</topic><topic>Cytochrome P-450 CYP3A - urine</topic><topic>Cytochrome P-450 CYP3A Inhibitors - administration & dosage</topic><topic>Cytochrome P-450 CYP3A Inhibitors - pharmacokinetics</topic><topic>Drug Interactions</topic><topic>Female</topic><topic>fentanyl</topic><topic>Fentanyl - administration & dosage</topic><topic>Fentanyl - analogs & derivatives</topic><topic>Fentanyl - blood</topic><topic>Fentanyl - metabolism</topic><topic>Fentanyl - pharmacokinetics</topic><topic>Fentanyl - urine</topic><topic>Healthy Volunteers</topic><topic>Humans</topic><topic>ketoconazole</topic><topic>Ketoconazole - administration & dosage</topic><topic>Ketoconazole - pharmacokinetics</topic><topic>Male</topic><topic>Midazolam - administration & dosage</topic><topic>Middle Aged</topic><topic>Naloxone - administration & dosage</topic><topic>Prospective Studies</topic><topic>Tandem Mass Spectrometry</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ziesenitz, Victoria C.</creatorcontrib><creatorcontrib>König, Sonja K.</creatorcontrib><creatorcontrib>Mahlke, Nina S.</creatorcontrib><creatorcontrib>Skopp, Gisela</creatorcontrib><creatorcontrib>Haefeli, Walter E.</creatorcontrib><creatorcontrib>Mikus, Gerd</creatorcontrib><collection>Istex</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>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ziesenitz, Victoria C.</au><au>König, Sonja K.</au><au>Mahlke, Nina S.</au><au>Skopp, Gisela</au><au>Haefeli, Walter E.</au><au>Mikus, Gerd</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacokinetic interaction of intravenous fentanyl with ketoconazole</atitle><jtitle>Journal of clinical pharmacology</jtitle><addtitle>The Journal of Clinical Pharmacology</addtitle><date>2015-06</date><risdate>2015</risdate><volume>55</volume><issue>6</issue><spage>708</spage><epage>717</epage><pages>708-717</pages><issn>0091-2700</issn><eissn>1552-4604</eissn><abstract>Fentanyl is primarily metabolized by CYP3A, but has also been suggested to act as a weak inhibitor of CYP3A. We investigated the influence of CYP3A inhibition by ketoconazole on the pharmacokinetics of intravenously administered fentanyl and the effect of fentanyl on CYP3A activity. A prospective, open‐label, randomized, monocentre, crossover study was conducted in 16 healthy volunteers. They received fentanyl alone (5 microgram per kilogram) or fentanyl plus ketoconazole (200 milligram orally B.I.D. over 2 days). Naloxone (2 × 0.2 milligram i.v.) was given simultaneously with fentanyl to mitigate any opioid effect. Midazolam was administered as a CYP3A probe drug. Fentanyl and its metabolites were quantified by LC/MS/MS in blood and urine samples obtained over 24 hour. Exposure of fentanyl (AUC0‐∞) was significantly increased to 133% and systemic clearance was reduced to 78% by ketoconazole, norfentanyl formation was significantly delayed and partial metabolic clearance decreased to 18%. Fentanyl had no influence on midazolam exposure and CYP3A activity whereas ketoconazole decreased CYP3A activity to 13%. Although fentanyl N‐dealkylation is substantially inhibited by ketoconazole, exposure of fentanyl itself increased by one third only. Clinically fentanyl dosage adjustments may become necessary when ketoconazole or other strong CYP3A inhibitors are given simultaneously. Fentanyl itself does not influence CYP3A activity.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>25651378</pmid><doi>10.1002/jcph.469</doi><tpages>10</tpages></addata></record> |
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| subjects | Administration, Intravenous Adult Analgesics, Opioid - administration & dosage Analgesics, Opioid - pharmacokinetics Chromatography, Liquid Cross-Over Studies CYP3A inhibition Cytochrome P-450 CYP3A - blood Cytochrome P-450 CYP3A - metabolism Cytochrome P-450 CYP3A - urine Cytochrome P-450 CYP3A Inhibitors - administration & dosage Cytochrome P-450 CYP3A Inhibitors - pharmacokinetics Drug Interactions Female fentanyl Fentanyl - administration & dosage Fentanyl - analogs & derivatives Fentanyl - blood Fentanyl - metabolism Fentanyl - pharmacokinetics Fentanyl - urine Healthy Volunteers Humans ketoconazole Ketoconazole - administration & dosage Ketoconazole - pharmacokinetics Male Midazolam - administration & dosage Middle Aged Naloxone - administration & dosage Prospective Studies Tandem Mass Spectrometry Young Adult |
| title | Pharmacokinetic interaction of intravenous fentanyl with ketoconazole |
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