We are analyzing https://link.springer.com/article/10.1007/s00280-005-0068-6.

Title:
Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics | Cancer Chemotherapy and Pharmacology
Description:
Sorafenib is a novel, small-molecule anticancer compound that inhibits tumor cell proliferation by targeting Raf in the Raf/MEK/ERK signalling pathway, and inhibits angiogenesis by targeting tyrosine kinases such as vascular-endothelial growth factor receptor (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor (PDGFR). In vitro microsomal data indicate that sorafenib is metabolized by two pathways: phase I oxidation mediated by cytochrome P450 (CYP) 3A4; and phase II conjugation mediated by UGT1A9. Approximately 50% of an orally administered dose is recovered as unchanged drug in the feces, due to either biliary excretion or lack of absorption. The aim of this study was to evaluate the effect of CYP3A inhibition by ketoconazole on sorafenib pharmacokinetics. This was an open-label, non-randomized, 2-period, one-way crossover study in sixteen healthy male subjects. A single 50 mg dose of sorafenib was administered alone (period 1) and in combination with ketoconazole 400 mg once daily (period 2) (ketoconazole was given for 7 days, and a single 50 mg sorafenib dose was administered concomitantly on day 4). No clinically relevant change in pharmacokinetics of sorafenib and no clinically relevant adverse events or laboratory abnormalities were observed in this study upon co-administration of the two drugs. Plasma concentrations of the main CYP3A4 generated metabolite, sorafenib N-oxide, decreased considerably upon ketoconazole co-administration. This effect is in accordance with the in vitro finding that CYP3A4 is the primary enzyme for sorafenib N-oxide formation. Further, these data indicate that blocking sorafenib metabolism by the CYP3A4 pathway will not lead to an increase in sorafenib exposure. This is consistent with data from a clinical mass-balance study that showed 15% of the administered dose was eliminated by glucuronidation, compared to less than 5% eliminated as oxidative metabolites. Since there was no increase in sorafenib exposure following concomitant administration of the highly potent CYP3A4 inhibitor ketoconazole with low dose sorafenib, it is postulated that higher therapeutic doses of sorafenib may be safely co-administered with ketoconazole, as well as with other inhibitors of CYP3A.
Website Age:
28 years and 1 months (reg. 1997-05-29).

Matching Content Categories {📚}

Education
Social Networks
Science

Content Management System {📝}

What CMS is link.springer.com built with?

Custom-built

No common CMS systems were detected on Link.springer.com, and no known web development framework was identified.

Traffic Estimate {📈}

What is the average monthly size of link.springer.com audience?

🌠 Phenomenal Traffic: 5M - 10M visitors per month

Based on our best estimate, this website will receive around 8,170,236 visitors per month in the current month.

check SE Ranking
check Ahrefs
check Similarweb
check Ubersuggest
check Semrush

How Does Link.springer.com Make Money? {💸}

We see no obvious way the site makes money.

While many websites aim to make money, others are created to share knowledge or showcase creativity. People build websites for various reasons. This could be one of them. Link.springer.com could be getting rich in stealth mode, or the way it's monetizing isn't detectable.

Keywords {🔍}

article, sorafenib, pubmed, cas, google, scholar, drug, cypa, data, ketoconazole, inhibitor, raf, kinase, clin, inhibition, clinical, pharmacol, pharmacokinetics, study, bay, patients, privacy, cookies, content, cancer, effect, factor, phase, cytochrome, administered, dose, solid, publish, research, search, lathia, growth, vitro, access, pharmacokinetic, tumors, human, hilger, ther, information, log, journal, pharmacology, lack, chetan,

Topics {✒️}

raf/mek/erk signalling pathway martin radtke & pavur sundaresan small-molecule anticancer compound month download article/chapter ketoconazole-mediated cyp3a inhibition raf kinase inhibitor gov/cber/gdlns/metabol sorafenib n-oxide formation active n-oxide metabolite article cancer chemotherapy clinical mass-balance study sorafenib clinical pharmacokinetics cytochrome p450 3a4 oxidative drug metabolism blocking sorafenib metabolism full article pdf targeting tyrosine kinases sorafenib n-oxide inhibits angiogenesis cytochrome p-450 3a privacy choices/manage cookies individualized drug treatment cytochrome p450 sorafenib pharmacokinetics low dose sorafenib cytotoxic drug activity raf kinase systemic antimycotics ketoconazole related subjects single 50 mg dose advanced solid malignancies european economic area clinically relevant change higher therapeutic doses von moltke ll advanced solid tumors conditions privacy policy article lathia check access antifungal imidazole derivatives instant access early clinical data cyp3a inhibition accepting optional cookies main content log high clearance drugs vitro microsomal data orally administered dose article log oxidation mediated

Schema {🗺️}

WebPage:
      mainEntity:
         headline:Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics
         description:Sorafenib is a novel, small-molecule anticancer compound that inhibits tumor cell proliferation by targeting Raf in the Raf/MEK/ERK signalling pathway, and inhibits angiogenesis by targeting tyrosine kinases such as vascular-endothelial growth factor receptor (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor (PDGFR). In vitro microsomal data indicate that sorafenib is metabolized by two pathways: phase I oxidation mediated by cytochrome P450 (CYP) 3A4; and phase II conjugation mediated by UGT1A9. Approximately 50% of an orally administered dose is recovered as unchanged drug in the feces, due to either biliary excretion or lack of absorption. The aim of this study was to evaluate the effect of CYP3A inhibition by ketoconazole on sorafenib pharmacokinetics. This was an open-label, non-randomized, 2-period, one-way crossover study in sixteen healthy male subjects. A single 50 mg dose of sorafenib was administered alone (period 1) and in combination with ketoconazole 400 mg once daily (period 2) (ketoconazole was given for 7 days, and a single 50 mg sorafenib dose was administered concomitantly on day 4). No clinically relevant change in pharmacokinetics of sorafenib and no clinically relevant adverse events or laboratory abnormalities were observed in this study upon co-administration of the two drugs. Plasma concentrations of the main CYP3A4 generated metabolite, sorafenib N-oxide, decreased considerably upon ketoconazole co-administration. This effect is in accordance with the in vitro finding that CYP3A4 is the primary enzyme for sorafenib N-oxide formation. Further, these data indicate that blocking sorafenib metabolism by the CYP3A4 pathway will not lead to an increase in sorafenib exposure. This is consistent with data from a clinical mass-balance study that showed 15% of the administered dose was eliminated by glucuronidation, compared to less than 5% eliminated as oxidative metabolites. Since there was no increase in sorafenib exposure following concomitant administration of the highly potent CYP3A4 inhibitor ketoconazole with low dose sorafenib, it is postulated that higher therapeutic doses of sorafenib may be safely co-administered with ketoconazole, as well as with other inhibitors of CYP3A.
         datePublished:2005-08-25T00:00:00Z
         dateModified:2005-08-25T00:00:00Z
         pageStart:685
         pageEnd:692
         sameAs:https://doi.org/10.1007/s00280-005-0068-6
         keywords:
            Sorafenib
            Ketoconazole
            CYP3A
            Drug interaction
            Anticancer
            Raf Kinase inhibitor
            Angiogenesis inhibitor
            Pharmacokinetics
            Oncology
            Pharmacology/Toxicology
            Cancer Research
         image:
            https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00280-005-0068-6/MediaObjects/280_2005_68_Fig1_HTML.gif
            https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00280-005-0068-6/MediaObjects/280_2005_68_Fig2_HTML.gif
            https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00280-005-0068-6/MediaObjects/280_2005_68_Fig3_HTML.gif
         isPartOf:
            name:Cancer Chemotherapy and Pharmacology
            issn:
               1432-0843
               0344-5704
            volumeNumber:57
            type:
               Periodical
               PublicationVolume
         publisher:
            name:Springer-Verlag
            logo:
               url:https://www.springernature.com/app-sn/public/images/logo-springernature.png
               type:ImageObject
            type:Organization
         author:
               name:Chetan Lathia
               affiliation:
                     name:Bayer Corporation
                     address:
                        name:Bayer Corporation, West Haven, USA
                        type:PostalAddress
                     type:Organization
               email:[email protected]
               type:Person
               name:John Lettieri
               affiliation:
                     name:Bayer Corporation
                     address:
                        name:Bayer Corporation, West Haven, USA
                        type:PostalAddress
                     type:Organization
               type:Person
               name:Frank Cihon
               affiliation:
                     name:Bayer Corporation
                     address:
                        name:Bayer Corporation, West Haven, USA
                        type:PostalAddress
                     type:Organization
               type:Person
               name:Martha Gallentine
               affiliation:
                     name:Bayer Corporation
                     address:
                        name:Bayer Corporation, West Haven, USA
                        type:PostalAddress
                     type:Organization
               type:Person
               name:Martin Radtke
               affiliation:
                     name:Bayer Corporation
                     address:
                        name:Bayer Corporation, West Haven, USA
                        type:PostalAddress
                     type:Organization
               type:Person
               name:Pavur Sundaresan
               affiliation:
                     name:Bayer Corporation
                     address:
                        name:Bayer Corporation, West Haven, USA
                        type:PostalAddress
                     type:Organization
               type:Person
         isAccessibleForFree:
         hasPart:
            isAccessibleForFree:
            cssSelector:.main-content
            type:WebPageElement
         type:ScholarlyArticle
      context:https://schema.org
ScholarlyArticle:
      headline:Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics
      description:Sorafenib is a novel, small-molecule anticancer compound that inhibits tumor cell proliferation by targeting Raf in the Raf/MEK/ERK signalling pathway, and inhibits angiogenesis by targeting tyrosine kinases such as vascular-endothelial growth factor receptor (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor (PDGFR). In vitro microsomal data indicate that sorafenib is metabolized by two pathways: phase I oxidation mediated by cytochrome P450 (CYP) 3A4; and phase II conjugation mediated by UGT1A9. Approximately 50% of an orally administered dose is recovered as unchanged drug in the feces, due to either biliary excretion or lack of absorption. The aim of this study was to evaluate the effect of CYP3A inhibition by ketoconazole on sorafenib pharmacokinetics. This was an open-label, non-randomized, 2-period, one-way crossover study in sixteen healthy male subjects. A single 50 mg dose of sorafenib was administered alone (period 1) and in combination with ketoconazole 400 mg once daily (period 2) (ketoconazole was given for 7 days, and a single 50 mg sorafenib dose was administered concomitantly on day 4). No clinically relevant change in pharmacokinetics of sorafenib and no clinically relevant adverse events or laboratory abnormalities were observed in this study upon co-administration of the two drugs. Plasma concentrations of the main CYP3A4 generated metabolite, sorafenib N-oxide, decreased considerably upon ketoconazole co-administration. This effect is in accordance with the in vitro finding that CYP3A4 is the primary enzyme for sorafenib N-oxide formation. Further, these data indicate that blocking sorafenib metabolism by the CYP3A4 pathway will not lead to an increase in sorafenib exposure. This is consistent with data from a clinical mass-balance study that showed 15% of the administered dose was eliminated by glucuronidation, compared to less than 5% eliminated as oxidative metabolites. Since there was no increase in sorafenib exposure following concomitant administration of the highly potent CYP3A4 inhibitor ketoconazole with low dose sorafenib, it is postulated that higher therapeutic doses of sorafenib may be safely co-administered with ketoconazole, as well as with other inhibitors of CYP3A.
      datePublished:2005-08-25T00:00:00Z
      dateModified:2005-08-25T00:00:00Z
      pageStart:685
      pageEnd:692
      sameAs:https://doi.org/10.1007/s00280-005-0068-6
      keywords:
         Sorafenib
         Ketoconazole
         CYP3A
         Drug interaction
         Anticancer
         Raf Kinase inhibitor
         Angiogenesis inhibitor
         Pharmacokinetics
         Oncology
         Pharmacology/Toxicology
         Cancer Research
      image:
         https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00280-005-0068-6/MediaObjects/280_2005_68_Fig1_HTML.gif
         https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00280-005-0068-6/MediaObjects/280_2005_68_Fig2_HTML.gif
         https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00280-005-0068-6/MediaObjects/280_2005_68_Fig3_HTML.gif
      isPartOf:
         name:Cancer Chemotherapy and Pharmacology
         issn:
            1432-0843
            0344-5704
         volumeNumber:57
         type:
            Periodical
            PublicationVolume
      publisher:
         name:Springer-Verlag
         logo:
            url:https://www.springernature.com/app-sn/public/images/logo-springernature.png
            type:ImageObject
         type:Organization
      author:
            name:Chetan Lathia
            affiliation:
                  name:Bayer Corporation
                  address:
                     name:Bayer Corporation, West Haven, USA
                     type:PostalAddress
                  type:Organization
            email:[email protected]
            type:Person
            name:John Lettieri
            affiliation:
                  name:Bayer Corporation
                  address:
                     name:Bayer Corporation, West Haven, USA
                     type:PostalAddress
                  type:Organization
            type:Person
            name:Frank Cihon
            affiliation:
                  name:Bayer Corporation
                  address:
                     name:Bayer Corporation, West Haven, USA
                     type:PostalAddress
                  type:Organization
            type:Person
            name:Martha Gallentine
            affiliation:
                  name:Bayer Corporation
                  address:
                     name:Bayer Corporation, West Haven, USA
                     type:PostalAddress
                  type:Organization
            type:Person
            name:Martin Radtke
            affiliation:
                  name:Bayer Corporation
                  address:
                     name:Bayer Corporation, West Haven, USA
                     type:PostalAddress
                  type:Organization
            type:Person
            name:Pavur Sundaresan
            affiliation:
                  name:Bayer Corporation
                  address:
                     name:Bayer Corporation, West Haven, USA
                     type:PostalAddress
                  type:Organization
            type:Person
      isAccessibleForFree:
      hasPart:
         isAccessibleForFree:
         cssSelector:.main-content
         type:WebPageElement
["Periodical","PublicationVolume"]:
      name:Cancer Chemotherapy and Pharmacology
      issn:
         1432-0843
         0344-5704
      volumeNumber:57
Organization:
      name:Springer-Verlag
      logo:
         url:https://www.springernature.com/app-sn/public/images/logo-springernature.png
         type:ImageObject
      name:Bayer Corporation
      address:
         name:Bayer Corporation, West Haven, USA
         type:PostalAddress
      name:Bayer Corporation
      address:
         name:Bayer Corporation, West Haven, USA
         type:PostalAddress
      name:Bayer Corporation
      address:
         name:Bayer Corporation, West Haven, USA
         type:PostalAddress
      name:Bayer Corporation
      address:
         name:Bayer Corporation, West Haven, USA
         type:PostalAddress
      name:Bayer Corporation
      address:
         name:Bayer Corporation, West Haven, USA
         type:PostalAddress
      name:Bayer Corporation
      address:
         name:Bayer Corporation, West Haven, USA
         type:PostalAddress
ImageObject:
      url:https://www.springernature.com/app-sn/public/images/logo-springernature.png
Person:
      name:Chetan Lathia
      affiliation:
            name:Bayer Corporation
            address:
               name:Bayer Corporation, West Haven, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
      name:John Lettieri
      affiliation:
            name:Bayer Corporation
            address:
               name:Bayer Corporation, West Haven, USA
               type:PostalAddress
            type:Organization
      name:Frank Cihon
      affiliation:
            name:Bayer Corporation
            address:
               name:Bayer Corporation, West Haven, USA
               type:PostalAddress
            type:Organization
      name:Martha Gallentine
      affiliation:
            name:Bayer Corporation
            address:
               name:Bayer Corporation, West Haven, USA
               type:PostalAddress
            type:Organization
      name:Martin Radtke
      affiliation:
            name:Bayer Corporation
            address:
               name:Bayer Corporation, West Haven, USA
               type:PostalAddress
            type:Organization
      name:Pavur Sundaresan
      affiliation:
            name:Bayer Corporation
            address:
               name:Bayer Corporation, West Haven, USA
               type:PostalAddress
            type:Organization
PostalAddress:
      name:Bayer Corporation, West Haven, USA
      name:Bayer Corporation, West Haven, USA
      name:Bayer Corporation, West Haven, USA
      name:Bayer Corporation, West Haven, USA
      name:Bayer Corporation, West Haven, USA
      name:Bayer Corporation, West Haven, USA
WebPageElement:
      isAccessibleForFree:
      cssSelector:.main-content

External Links {🔗}(76)

Analytics and Tracking {📊}

Google Tag Manager

Libraries {📚}

Clipboard.js
Prism.js

CDN Services {📦}

Crossref

4.08s.

LINK . SPRINGER . COM {}