{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1361981469028480128.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.1046/j.0306-5251.2003.01862.x"}},{"identifier":{"@type":"URI","@value":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1046%2Fj.0306-5251.2003.01862.x"}},{"identifier":{"@type":"URI","@value":"https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1046/j.0306-5251.2003.01862.x"}}],"dc:title":[{"@value":"CYP2C8 and CYP3A4 are the principal enzymes involved in the human <i>in vitro</i> biotransformation of the insulin secretagogue repaglinide"}],"description":[{"type":"abstract","notation":[{"@value":"<jats:p><jats:bold>Aims </jats:bold> To identify the principal human cytochrome P450 (CYP) enzyme(s) responsible for the human <jats:italic>in vitro</jats:italic> biotransformation of repaglinide. Previous experiments have identified CYP3A4 as being mainly responsible for the <jats:italic>in vitro</jats:italic> metabolism of repaglinide, but the results of clinical investigations have suggested that more than one enzyme may be involved in repaglinide biotransformation.</jats:p><jats:p><jats:bold>Methods </jats:bold> [<jats:sup>14</jats:sup>C]‐Repaglinide was incubated with recombinant CYP and with human liver microsomes (HLM) from individual donors in the presence of inhibitory antibodies specific for individual CYP enzymes. Metabolites, measured by high‐performance liquid chromatography (HPLC) with on‐line radiochemical detection, were identified by liquid chromatography‐mass spectrophotometry (LC‐MS) and LC‐MS coupled on‐line to a nuclear magnetic resonance spectrometer (LC‐MS‐NMR).</jats:p><jats:p><jats:bold>Results </jats:bold> CYP3A4 and CYP2C8 were found to be responsible for the conversion of repaglinide into its two primary metabolites, M4 (resulting from hydroxylation on the piperidine ring system) and M1 (an aromatic amine). Specific inhibitory monoclonal antibodies against CYP3A4 and CYP2C8 significantly inhibited (> 71%) formation of M4 and M1 in HLM. In a panel of HLM from 12 individual donors formation of M4 and M1 varied from approximately 160–880 pmol min<jats:sup>−1</jats:sup> mg<jats:sup>−1</jats:sup> protein and from 100–1110 pmol min<jats:sup>−1</jats:sup> mg<jats:sup>−1</jats:sup> protein, respectively. The major metabolite generated by CYP2C8 was found to be M4. The rate of formation of this metabolite in HLM correlated significantly with paclitaxel 6α‐hydroxylation (<jats:italic>r</jats:italic><jats:sub>s</jats:sub> = 0.80; <jats:italic>P</jats:italic> = 0.0029). Two other minor metabolites were also detected. One of them was M1 and the other was repaglinide hydroxylated on the isopropyl moiety (M0‐OH). The rate of formation of M4 in CYP2C8 Supersomes<jats:sup>TM</jats:sup> was 2.5 pmol min<jats:sup>−1</jats:sup> pmol<jats:sup>−1</jats:sup> CYP enzyme and only about 0.1 pmol min<jats:sup>−1</jats:sup> pmol<jats:sup>−1</jats:sup> CYP enzyme in CYP3A4 Supersomes<jats:sup>TM</jats:sup>. The major metabolite generated by CYP3A4 was M1. The rate of formation of this metabolite in HLM correlated significantly with testosterone 6β‐hydroxylation (<jats:italic>r</jats:italic><jats:sub>s</jats:sub> = 0.90; <jats:italic>P</jats:italic> = 0.0002). Three other metabolites were identified, namely, M0‐OH, M2 (a dicarboxylic acid formed by oxidative opening of the piperidine ring) and M5. The rate of M1 formation in CYP3A4 Supersomes<jats:sup>TM</jats:sup> was 1.6 pmol min<jats:sup>−1</jats:sup> pmol<jats:sup>−1</jats:sup> CYP enzyme but in CYP2C8 Super‐somes<jats:sup>TM</jats:sup> it was only approximately 0.4 pmol min<jats:sup>−1</jats:sup> pmol<jats:sup>−1</jats:sup> CYP enzyme.</jats:p><jats:p><jats:bold>Conclusions </jats:bold> The results confirm an important role for both CYP3A4 and CYP2C8 in the human <jats:italic>in vitro</jats:italic> biotransformation of repaglinide. This dual CYP biotransformation may have consequences for the clinical pharmacokinetics and drug‐drug interactions involving repaglinide if one CYP pathway has sufficient capacity to compensate if the other is inhibited.</jats:p>"}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1381981469028480131","@type":"Researcher","foaf:name":[{"@value":"Tanja Busk Bidstrup"}]},{"@id":"https://cir.nii.ac.jp/crid/1381981469028480129","@type":"Researcher","foaf:name":[{"@value":"Inga Bjørnsdottir"}]},{"@id":"https://cir.nii.ac.jp/crid/1381981469028480132","@type":"Researcher","foaf:name":[{"@value":"Ulla Grove Sidelmann"}]},{"@id":"https://cir.nii.ac.jp/crid/1381981469028480128","@type":"Researcher","foaf:name":[{"@value":"Mikael Søndergård Thomsen"}]},{"@id":"https://cir.nii.ac.jp/crid/1381981469028480130","@type":"Researcher","foaf:name":[{"@value":"Kristian Tage Hansen"}]}],"publication":{"publicationIdentifier":[{"@type":"PISSN","@value":"03065251"},{"@type":"EISSN","@value":"13652125"}],"prism:publicationName":[{"@value":"British Journal of Clinical Pharmacology"}],"dc:publisher":[{"@value":"Wiley"}],"prism:publicationDate":"2003-07-22","prism:volume":"56","prism:number":"3","prism:startingPage":"305","prism:endingPage":"314"},"reviewed":"false","dc:rights":["http://onlinelibrary.wiley.com/termsAndConditions#vor"],"url":[{"@id":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1046%2Fj.0306-5251.2003.01862.x"},{"@id":"https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1046/j.0306-5251.2003.01862.x"}],"createdAt":"2003-08-14","modifiedAt":"2023-10-13","relatedProduct":[{"@id":"https://cir.nii.ac.jp/crid/1360004235933785088","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Analysis of the Repaglinide Concentration Increase Produced by Gemfibrozil and 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Contribution of CYP2C8 and CYP3A4 in Repaglinide Metabolism by Human Liver Microsomes Under Various Buffer Conditions"}]},{"@id":"https://cir.nii.ac.jp/crid/1360567182509681280","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Quantitative Analysis of Complex Drug–Drug Interactions Between Repaglinide and Cyclosporin A/Gemfibrozil Using Physiologically Based Pharmacokinetic Models With In Vitro Transporter/Enzyme Inhibition Data"}]},{"@id":"https://cir.nii.ac.jp/crid/1360848657048251008","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Strategies to improve the prediction accuracy of hepatic intrinsic clearance of three antidiabetic drugs: Application of the extended clearance concept and consideration of the effect of albumin on CYP2C metabolism and OATP1B-mediated hepatic uptake"}]},{"@id":"https://cir.nii.ac.jp/crid/1360861288769678208","@type":"Article","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Construction of a fused grid-based CYP2C8-Template system and the application"}]},{"@id":"https://cir.nii.ac.jp/crid/1362823123421175040","@type":"Article","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Identification and quantitation of enzyme and transporter contributions to hepatic clearance for the assessment of potential drug-drug interactions"}]},{"@id":"https://cir.nii.ac.jp/crid/1390001204631316480","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@language":"en","@value":"Co-administration of Fluvastatin and CYP3A4 and CYP2C8 Inhibitors May Increase the Exposure to Fluvastatin in Carriers of CYP2C9 Genetic Variants"}]},{"@id":"https://cir.nii.ac.jp/crid/1390282679147192192","@type":"Article","resourceType":"学術雑誌論文(journal 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