Erythromycin increases plasma concentrations of α‐dihydroergocryptine in humans
Objective Our objective was to investigate the potential for relevant pharmacotherapeutic interaction between cytochrome P4503A4 (CYP3A4)–inhibiting agents such as erythromycin and the dopamine agonist α‐dihydroergocryptine (DHEC). Methods The study was carried out as a single‐center, controlled, no...
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| Veröffentlicht in: | Clinical pharmacology and therapeutics 2001-08, Vol.70 (2), p.142-148 |
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| creator | Mey, Christian Althaus, Michael Ezan, Eric Retzow, Angelika |
| description | Objective
Our objective was to investigate the potential for relevant pharmacotherapeutic interaction between cytochrome P4503A4 (CYP3A4)–inhibiting agents such as erythromycin and the dopamine agonist α‐dihydroergocryptine (DHEC).
Methods
The study was carried out as a single‐center, controlled, nonblinded, 2‐way crossover clinical trial with randomly allocated period‐balanced sequences, investigating two treatments of a single oral dose of 10 mg DHEC (on the morning of day 1), once administered alone (reference), once along with a 4‐day treatment (days −2 to 1) of 500 mg erythromycin 3 times daily. Periods were separated by a washout of at least 14 days. Nine healthy white male volunteers, 22 to 42 years old, with a body weight range of 58 to 90 kg (body mass index, 20.2–25.1 kg · m−2) began the study. One subject discontinued prematurely, and 8 concluded the study in accordance with the study protocol.
Results
The plasma and urinary pharmacokinetics of DHEC and its metabolites were characterized by a large variability. Concomitant treatment with erythromycin led to respective increases of 9.5 (95% confidence interval [CI], 6.5 to 13.9) and 16.5 (95% CI, 8.7 to 31.5) times the maximum observed plasma drug concentration and the area under the time course of the plasma concentrations up to the last quantifiable concentration after dosing of unchanged DHEC (determined by radioimmunoassay). The 24‐hour urinary excretion was on average 11 times larger (95% CI, 5.9 to 20.7). Qualitatively similar findings were recorded for the total of DHEC plus metabolites (as determined by enzyme immunoassay).
Conclusions
The concomitant use of erythromycin or similarly CYP3A4‐inhibiting agents along with direct dopaminergic agonists such as the ergoline DHEC may cause a clinically relevant increase in pharmacokinetic exposure, which may induce exaggerated dopaminergic effects.
Clinical Pharmacology & Therapeutics (2001) 70, 142–148; doi: 10.1067/mcp.2001.117286 |
| doi_str_mv | 10.1067/mcp.2001.117286 |
| format | Article |
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Our objective was to investigate the potential for relevant pharmacotherapeutic interaction between cytochrome P4503A4 (CYP3A4)–inhibiting agents such as erythromycin and the dopamine agonist α‐dihydroergocryptine (DHEC).
Methods
The study was carried out as a single‐center, controlled, nonblinded, 2‐way crossover clinical trial with randomly allocated period‐balanced sequences, investigating two treatments of a single oral dose of 10 mg DHEC (on the morning of day 1), once administered alone (reference), once along with a 4‐day treatment (days −2 to 1) of 500 mg erythromycin 3 times daily. Periods were separated by a washout of at least 14 days. Nine healthy white male volunteers, 22 to 42 years old, with a body weight range of 58 to 90 kg (body mass index, 20.2–25.1 kg · m−2) began the study. One subject discontinued prematurely, and 8 concluded the study in accordance with the study protocol.
Results
The plasma and urinary pharmacokinetics of DHEC and its metabolites were characterized by a large variability. Concomitant treatment with erythromycin led to respective increases of 9.5 (95% confidence interval [CI], 6.5 to 13.9) and 16.5 (95% CI, 8.7 to 31.5) times the maximum observed plasma drug concentration and the area under the time course of the plasma concentrations up to the last quantifiable concentration after dosing of unchanged DHEC (determined by radioimmunoassay). The 24‐hour urinary excretion was on average 11 times larger (95% CI, 5.9 to 20.7). Qualitatively similar findings were recorded for the total of DHEC plus metabolites (as determined by enzyme immunoassay).
Conclusions
The concomitant use of erythromycin or similarly CYP3A4‐inhibiting agents along with direct dopaminergic agonists such as the ergoline DHEC may cause a clinically relevant increase in pharmacokinetic exposure, which may induce exaggerated dopaminergic effects.
Clinical Pharmacology & Therapeutics (2001) 70, 142–148; doi: 10.1067/mcp.2001.117286</description><identifier>ISSN: 0009-9236</identifier><identifier>EISSN: 1532-6535</identifier><identifier>DOI: 10.1067/mcp.2001.117286</identifier><identifier>PMID: 11503008</identifier><identifier>CODEN: CLPTAT</identifier><language>eng</language><publisher>New York, NY: Nature Publishing</publisher><subject>Administration, Oral ; Adult ; Analysis of Variance ; Anti-Bacterial Agents - pharmacology ; Anticonvulsants. Antiepileptics. Antiparkinson agents ; Area Under Curve ; Biological and medical sciences ; Cross-Over Studies ; Cytochrome P-450 CYP3A ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System - metabolism ; Dihydroergotoxine - urine ; Dopamine Agonists - urine ; Drug Administration Schedule ; Enzyme Inhibitors - administration & dosage ; Enzyme Inhibitors - pharmacology ; Erythromycin - administration & dosage ; Erythromycin - pharmacology ; Humans ; Male ; Medical sciences ; Mixed Function Oxygenases - antagonists & inhibitors ; Mixed Function Oxygenases - metabolism ; Neuropharmacology ; Pharmacology. Drug treatments ; Radioimmunoassay</subject><ispartof>Clinical pharmacology and therapeutics, 2001-08, Vol.70 (2), p.142-148</ispartof><rights>2001 American Society for Clinical Pharmacology and Therapeutics</rights><rights>2001 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1067%2Fmcp.2001.117286$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1067%2Fmcp.2001.117286$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1107456$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11503008$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mey, Christian</creatorcontrib><creatorcontrib>Althaus, Michael</creatorcontrib><creatorcontrib>Ezan, Eric</creatorcontrib><creatorcontrib>Retzow, Angelika</creatorcontrib><title>Erythromycin increases plasma concentrations of α‐dihydroergocryptine in humans</title><title>Clinical pharmacology and therapeutics</title><addtitle>Clin Pharmacol Ther</addtitle><description>Objective
Our objective was to investigate the potential for relevant pharmacotherapeutic interaction between cytochrome P4503A4 (CYP3A4)–inhibiting agents such as erythromycin and the dopamine agonist α‐dihydroergocryptine (DHEC).
Methods
The study was carried out as a single‐center, controlled, nonblinded, 2‐way crossover clinical trial with randomly allocated period‐balanced sequences, investigating two treatments of a single oral dose of 10 mg DHEC (on the morning of day 1), once administered alone (reference), once along with a 4‐day treatment (days −2 to 1) of 500 mg erythromycin 3 times daily. Periods were separated by a washout of at least 14 days. Nine healthy white male volunteers, 22 to 42 years old, with a body weight range of 58 to 90 kg (body mass index, 20.2–25.1 kg · m−2) began the study. One subject discontinued prematurely, and 8 concluded the study in accordance with the study protocol.
Results
The plasma and urinary pharmacokinetics of DHEC and its metabolites were characterized by a large variability. Concomitant treatment with erythromycin led to respective increases of 9.5 (95% confidence interval [CI], 6.5 to 13.9) and 16.5 (95% CI, 8.7 to 31.5) times the maximum observed plasma drug concentration and the area under the time course of the plasma concentrations up to the last quantifiable concentration after dosing of unchanged DHEC (determined by radioimmunoassay). The 24‐hour urinary excretion was on average 11 times larger (95% CI, 5.9 to 20.7). Qualitatively similar findings were recorded for the total of DHEC plus metabolites (as determined by enzyme immunoassay).
Conclusions
The concomitant use of erythromycin or similarly CYP3A4‐inhibiting agents along with direct dopaminergic agonists such as the ergoline DHEC may cause a clinically relevant increase in pharmacokinetic exposure, which may induce exaggerated dopaminergic effects.
Clinical Pharmacology & Therapeutics (2001) 70, 142–148; doi: 10.1067/mcp.2001.117286</description><subject>Administration, Oral</subject><subject>Adult</subject><subject>Analysis of Variance</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Anticonvulsants. Antiepileptics. Antiparkinson agents</subject><subject>Area Under Curve</subject><subject>Biological and medical sciences</subject><subject>Cross-Over Studies</subject><subject>Cytochrome P-450 CYP3A</subject><subject>Cytochrome P-450 Enzyme Inhibitors</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Dihydroergotoxine - urine</subject><subject>Dopamine Agonists - urine</subject><subject>Drug Administration Schedule</subject><subject>Enzyme Inhibitors - administration & dosage</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Erythromycin - administration & dosage</subject><subject>Erythromycin - pharmacology</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mixed Function Oxygenases - antagonists & inhibitors</subject><subject>Mixed Function Oxygenases - metabolism</subject><subject>Neuropharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Radioimmunoassay</subject><issn>0009-9236</issn><issn>1532-6535</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkc1OwzAMgCMEYmNw5oZ6QNw6nKZJWm6oGj_SJCY0zlGapiyoTUvSCfXGI_AqvAgPwZPQaUNwsmx_tmR_CJ1imGJg_LJW7TQCwFOMeZSwPTTGlEQho4TuozEApGEaETZCR96_DGmcJskhGmFMgQAkY_Q4c323ck3dK2MDY5XT0msftJX0tQxUY5W2nZOdaawPmjL4-vx-_yjMqi9co91zo1zfdsbqYTZYrWtp_TE6KGXl9ckuTtDTzWyZ3YXzh9v77HoetlHCWcghx2WiS1yABMZ0EROWDlekMVNFjhONieQlxzpOJKWK8CJncZnnRFNW0gjIBF1s97aueV1r34naeKWrSlrdrL3gGFLCOB7Asx24zmtdiNaZWrpe_H5hAM53gPRKVqWTVhn_jwMeUzZgV1vszVS6_2uD2LgQgwuxcSG2LkS2WGbzxXJT4oz8AGBegB8</recordid><startdate>200108</startdate><enddate>200108</enddate><creator>Mey, Christian</creator><creator>Althaus, Michael</creator><creator>Ezan, Eric</creator><creator>Retzow, Angelika</creator><general>Nature Publishing</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>200108</creationdate><title>Erythromycin increases plasma concentrations of α‐dihydroergocryptine in humans</title><author>Mey, Christian ; Althaus, Michael ; Ezan, Eric ; Retzow, Angelika</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p2876-70b1f8ef1d0a066ed4369172946cdb18e13a7f71e48a55c37db64fbb3e56f5203</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Administration, Oral</topic><topic>Adult</topic><topic>Analysis of Variance</topic><topic>Anti-Bacterial Agents - pharmacology</topic><topic>Anticonvulsants. Antiepileptics. Antiparkinson agents</topic><topic>Area Under Curve</topic><topic>Biological and medical sciences</topic><topic>Cross-Over Studies</topic><topic>Cytochrome P-450 CYP3A</topic><topic>Cytochrome P-450 Enzyme Inhibitors</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>Dihydroergotoxine - urine</topic><topic>Dopamine Agonists - urine</topic><topic>Drug Administration Schedule</topic><topic>Enzyme Inhibitors - administration & dosage</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Erythromycin - administration & dosage</topic><topic>Erythromycin - pharmacology</topic><topic>Humans</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mixed Function Oxygenases - antagonists & inhibitors</topic><topic>Mixed Function Oxygenases - metabolism</topic><topic>Neuropharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Radioimmunoassay</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mey, Christian</creatorcontrib><creatorcontrib>Althaus, Michael</creatorcontrib><creatorcontrib>Ezan, Eric</creatorcontrib><creatorcontrib>Retzow, Angelika</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>MEDLINE - Academic</collection><jtitle>Clinical pharmacology and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mey, Christian</au><au>Althaus, Michael</au><au>Ezan, Eric</au><au>Retzow, Angelika</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Erythromycin increases plasma concentrations of α‐dihydroergocryptine in humans</atitle><jtitle>Clinical pharmacology and therapeutics</jtitle><addtitle>Clin Pharmacol Ther</addtitle><date>2001-08</date><risdate>2001</risdate><volume>70</volume><issue>2</issue><spage>142</spage><epage>148</epage><pages>142-148</pages><issn>0009-9236</issn><eissn>1532-6535</eissn><coden>CLPTAT</coden><abstract>Objective
Our objective was to investigate the potential for relevant pharmacotherapeutic interaction between cytochrome P4503A4 (CYP3A4)–inhibiting agents such as erythromycin and the dopamine agonist α‐dihydroergocryptine (DHEC).
Methods
The study was carried out as a single‐center, controlled, nonblinded, 2‐way crossover clinical trial with randomly allocated period‐balanced sequences, investigating two treatments of a single oral dose of 10 mg DHEC (on the morning of day 1), once administered alone (reference), once along with a 4‐day treatment (days −2 to 1) of 500 mg erythromycin 3 times daily. Periods were separated by a washout of at least 14 days. Nine healthy white male volunteers, 22 to 42 years old, with a body weight range of 58 to 90 kg (body mass index, 20.2–25.1 kg · m−2) began the study. One subject discontinued prematurely, and 8 concluded the study in accordance with the study protocol.
Results
The plasma and urinary pharmacokinetics of DHEC and its metabolites were characterized by a large variability. Concomitant treatment with erythromycin led to respective increases of 9.5 (95% confidence interval [CI], 6.5 to 13.9) and 16.5 (95% CI, 8.7 to 31.5) times the maximum observed plasma drug concentration and the area under the time course of the plasma concentrations up to the last quantifiable concentration after dosing of unchanged DHEC (determined by radioimmunoassay). The 24‐hour urinary excretion was on average 11 times larger (95% CI, 5.9 to 20.7). Qualitatively similar findings were recorded for the total of DHEC plus metabolites (as determined by enzyme immunoassay).
Conclusions
The concomitant use of erythromycin or similarly CYP3A4‐inhibiting agents along with direct dopaminergic agonists such as the ergoline DHEC may cause a clinically relevant increase in pharmacokinetic exposure, which may induce exaggerated dopaminergic effects.
Clinical Pharmacology & Therapeutics (2001) 70, 142–148; doi: 10.1067/mcp.2001.117286</abstract><cop>New York, NY</cop><pub>Nature Publishing</pub><pmid>11503008</pmid><doi>10.1067/mcp.2001.117286</doi><tpages>7</tpages></addata></record> |
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| subjects | Administration, Oral Adult Analysis of Variance Anti-Bacterial Agents - pharmacology Anticonvulsants. Antiepileptics. Antiparkinson agents Area Under Curve Biological and medical sciences Cross-Over Studies Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 Enzyme System - metabolism Dihydroergotoxine - urine Dopamine Agonists - urine Drug Administration Schedule Enzyme Inhibitors - administration & dosage Enzyme Inhibitors - pharmacology Erythromycin - administration & dosage Erythromycin - pharmacology Humans Male Medical sciences Mixed Function Oxygenases - antagonists & inhibitors Mixed Function Oxygenases - metabolism Neuropharmacology Pharmacology. Drug treatments Radioimmunoassay |
| title | Erythromycin increases plasma concentrations of α‐dihydroergocryptine in humans |
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