A comparison of relative abundance, activity factor and inhibitory monoclonal antibody approaches in the characterization of human CYP enzymology
Aims The objective of this study was to evaluate the potential uses of relative abundance, relative activity approaches and inhibitory monoclonal antibodies (mAbs) in the characterization of CYP enzymology in early drug discovery. Methods Intrinsic clearance estimates for the oxidation of ethoxyreso...
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| Veröffentlicht in: | British journal of clinical pharmacology 2003-02, Vol.55 (2), p.175-181 |
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| creator | Soars, Matthew G. Gelboin, Harry V. Krausz, Kristopher W. Riley, Robert J. |
| description | Aims The objective of this study was to evaluate the potential uses of relative abundance, relative activity approaches and inhibitory monoclonal antibodies (mAbs) in the characterization of CYP enzymology in early drug discovery.
Methods Intrinsic clearance estimates for the oxidation of ethoxyresorufin (a selective probe of CYP1A2 activity), tolbutamide (CYP2C9), S‐mephenytoin (CYPC19), dextromethorphan (CYP2D6) and testosterone (CYP3A4) were used to determine relative activity factors (RAFs). CLint values were determined for the metabolism of 14 drugs in human liver microsomes (HLM) and for these major CYPs. The relative contribution of each individual CYP to the oxidation of each drug was then assessed using relative abundance and activity techniques in addition to inhibitory mAbs.
Results Relative abundance and activity methods as well as inhibitory mAbs qualitatively assigned the same CYP isoform as predominantly responsible for the clearance of each drug by HLM. Metabolism catalysed by CYP1A2, 2C9, 2D6 and 3A4 was also predicted to be quantitatively similar using both abundance and activity techniques. However, the relative contribution of the polymorphic CYP2C19 appeared to be over‐estimated approximately two‐fold using recombinant CYP compared with that from the HLM and mAb approach.
Conclusions All three methods investigated in this study appear suitable for use in the characterization of the CYP metabolism of new chemical entities produced during early drug discovery. |
| doi_str_mv | 10.1046/j.1365-2125.2003.01721.x |
| format | Article |
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Methods Intrinsic clearance estimates for the oxidation of ethoxyresorufin (a selective probe of CYP1A2 activity), tolbutamide (CYP2C9), S‐mephenytoin (CYPC19), dextromethorphan (CYP2D6) and testosterone (CYP3A4) were used to determine relative activity factors (RAFs). CLint values were determined for the metabolism of 14 drugs in human liver microsomes (HLM) and for these major CYPs. The relative contribution of each individual CYP to the oxidation of each drug was then assessed using relative abundance and activity techniques in addition to inhibitory mAbs.
Results Relative abundance and activity methods as well as inhibitory mAbs qualitatively assigned the same CYP isoform as predominantly responsible for the clearance of each drug by HLM. Metabolism catalysed by CYP1A2, 2C9, 2D6 and 3A4 was also predicted to be quantitatively similar using both abundance and activity techniques. However, the relative contribution of the polymorphic CYP2C19 appeared to be over‐estimated approximately two‐fold using recombinant CYP compared with that from the HLM and mAb approach.
Conclusions All three methods investigated in this study appear suitable for use in the characterization of the CYP metabolism of new chemical entities produced during early drug discovery.</description><identifier>ISSN: 0306-5251</identifier><identifier>EISSN: 1365-2125</identifier><identifier>DOI: 10.1046/j.1365-2125.2003.01721.x</identifier><identifier>PMID: 12580989</identifier><identifier>CODEN: BCPHBM</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Science Ltd</publisher><subject>Analytical, structural and metabolic biochemistry ; Antibodies, Monoclonal - pharmacology ; Biological and medical sciences ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System - analysis ; Cytochrome P-450 Enzyme System - metabolism ; Drug Design ; Drug Disposition ; Enzymes and enzyme inhibitors ; Fundamental and applied biological sciences. Psychology ; HLM monoclonal antibody ; Humans ; intrinsic clearance ; Oxidoreductases ; Phenotype ; reaction phenotyping ; recombinant CYP</subject><ispartof>British journal of clinical pharmacology, 2003-02, Vol.55 (2), p.175-181</ispartof><rights>2003 INIST-CNRS</rights><rights>2003 Blackwell Science Ltd 2003</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5661-270bb9a64ba8b596c946a6ffc5dde46b6212dc69e23310e7b87273d6e77a5ed43</citedby><cites>FETCH-LOGICAL-c5661-270bb9a64ba8b596c946a6ffc5dde46b6212dc69e23310e7b87273d6e77a5ed43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1046%2Fj.1365-2125.2003.01721.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1046%2Fj.1365-2125.2003.01721.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14626669$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12580989$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Soars, Matthew G.</creatorcontrib><creatorcontrib>Gelboin, Harry V.</creatorcontrib><creatorcontrib>Krausz, Kristopher W.</creatorcontrib><creatorcontrib>Riley, Robert J.</creatorcontrib><title>A comparison of relative abundance, activity factor and inhibitory monoclonal antibody approaches in the characterization of human CYP enzymology</title><title>British journal of clinical pharmacology</title><addtitle>Br J Clin Pharmacol</addtitle><description>Aims The objective of this study was to evaluate the potential uses of relative abundance, relative activity approaches and inhibitory monoclonal antibodies (mAbs) in the characterization of CYP enzymology in early drug discovery.
Methods Intrinsic clearance estimates for the oxidation of ethoxyresorufin (a selective probe of CYP1A2 activity), tolbutamide (CYP2C9), S‐mephenytoin (CYPC19), dextromethorphan (CYP2D6) and testosterone (CYP3A4) were used to determine relative activity factors (RAFs). CLint values were determined for the metabolism of 14 drugs in human liver microsomes (HLM) and for these major CYPs. The relative contribution of each individual CYP to the oxidation of each drug was then assessed using relative abundance and activity techniques in addition to inhibitory mAbs.
Results Relative abundance and activity methods as well as inhibitory mAbs qualitatively assigned the same CYP isoform as predominantly responsible for the clearance of each drug by HLM. Metabolism catalysed by CYP1A2, 2C9, 2D6 and 3A4 was also predicted to be quantitatively similar using both abundance and activity techniques. However, the relative contribution of the polymorphic CYP2C19 appeared to be over‐estimated approximately two‐fold using recombinant CYP compared with that from the HLM and mAb approach.
Conclusions All three methods investigated in this study appear suitable for use in the characterization of the CYP metabolism of new chemical entities produced during early drug discovery.</description><subject>Analytical, structural and metabolic biochemistry</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cytochrome P-450 Enzyme Inhibitors</subject><subject>Cytochrome P-450 Enzyme System - analysis</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Drug Design</subject><subject>Drug Disposition</subject><subject>Enzymes and enzyme inhibitors</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>HLM monoclonal antibody</subject><subject>Humans</subject><subject>intrinsic clearance</subject><subject>Oxidoreductases</subject><subject>Phenotype</subject><subject>reaction phenotyping</subject><subject>recombinant CYP</subject><issn>0306-5251</issn><issn>1365-2125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1u1DAUhS0EosPAKyBvYEWCHcdOsgCpjPiTKtEFLFhZN47TeOTYwc6Upm_BG-MwoxZ2rHztc-49V_4QwpTklJTi9T6nTPCsoAXPC0JYTmhV0PzmAdrcCQ_RhjAiMl5weoaexLgnhDIq-GN0luSaNHWzQb_OsfLjBMFE77DvcdAWZnOtMbQH14FT-hUGlV7MvOA-VT5gcB02bjCtSbcFj955Zb0Dm5TZtL5bMExT8KAGHZMTz4PGaoCQ2nUwtyngGDYcRnB49_0Sa3e7jN76q-UpetSDjfrZ6dyibx_ef919yi6-fPy8O7_IFBeCZkVF2rYBUbZQt7wRqikFiL5XvOt0KVqR_qBTotEFY5Toqq2romKd0FUFXHcl26K3x7nToR11p7SbA1g5BTNCWKQHI_9VnBnklb-WtG7KijVpwMvTgOB_HHSc5Wii0taC0_4QZcUIbXiK36L6aFTBxxh0fxdCiVx5yr1csckVm1x5yj885U1qff73kveNJ4DJ8OJkgKjA9iERM_HeV4pCCLH63hx9P43Vy38vIN_tLteK_QYWgcBs</recordid><startdate>200302</startdate><enddate>200302</enddate><creator>Soars, Matthew G.</creator><creator>Gelboin, Harry V.</creator><creator>Krausz, Kristopher W.</creator><creator>Riley, Robert J.</creator><general>Blackwell Science Ltd</general><general>Blackwell Science</general><general>Blackwell Science Inc</general><scope>IQODW</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>200302</creationdate><title>A comparison of relative abundance, activity factor and inhibitory monoclonal antibody approaches in the characterization of human CYP enzymology</title><author>Soars, Matthew G. ; Gelboin, Harry V. ; Krausz, Kristopher W. ; Riley, Robert J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5661-270bb9a64ba8b596c946a6ffc5dde46b6212dc69e23310e7b87273d6e77a5ed43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Analytical, structural and metabolic biochemistry</topic><topic>Antibodies, Monoclonal - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cytochrome P-450 Enzyme Inhibitors</topic><topic>Cytochrome P-450 Enzyme System - analysis</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>Drug Design</topic><topic>Drug Disposition</topic><topic>Enzymes and enzyme inhibitors</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>HLM monoclonal antibody</topic><topic>Humans</topic><topic>intrinsic clearance</topic><topic>Oxidoreductases</topic><topic>Phenotype</topic><topic>reaction phenotyping</topic><topic>recombinant CYP</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Soars, Matthew G.</creatorcontrib><creatorcontrib>Gelboin, Harry V.</creatorcontrib><creatorcontrib>Krausz, Kristopher W.</creatorcontrib><creatorcontrib>Riley, Robert J.</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>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Soars, Matthew G.</au><au>Gelboin, Harry V.</au><au>Krausz, Kristopher W.</au><au>Riley, Robert J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A comparison of relative abundance, activity factor and inhibitory monoclonal antibody approaches in the characterization of human CYP enzymology</atitle><jtitle>British journal of clinical pharmacology</jtitle><addtitle>Br J Clin Pharmacol</addtitle><date>2003-02</date><risdate>2003</risdate><volume>55</volume><issue>2</issue><spage>175</spage><epage>181</epage><pages>175-181</pages><issn>0306-5251</issn><eissn>1365-2125</eissn><coden>BCPHBM</coden><abstract>Aims The objective of this study was to evaluate the potential uses of relative abundance, relative activity approaches and inhibitory monoclonal antibodies (mAbs) in the characterization of CYP enzymology in early drug discovery.
Methods Intrinsic clearance estimates for the oxidation of ethoxyresorufin (a selective probe of CYP1A2 activity), tolbutamide (CYP2C9), S‐mephenytoin (CYPC19), dextromethorphan (CYP2D6) and testosterone (CYP3A4) were used to determine relative activity factors (RAFs). CLint values were determined for the metabolism of 14 drugs in human liver microsomes (HLM) and for these major CYPs. The relative contribution of each individual CYP to the oxidation of each drug was then assessed using relative abundance and activity techniques in addition to inhibitory mAbs.
Results Relative abundance and activity methods as well as inhibitory mAbs qualitatively assigned the same CYP isoform as predominantly responsible for the clearance of each drug by HLM. Metabolism catalysed by CYP1A2, 2C9, 2D6 and 3A4 was also predicted to be quantitatively similar using both abundance and activity techniques. However, the relative contribution of the polymorphic CYP2C19 appeared to be over‐estimated approximately two‐fold using recombinant CYP compared with that from the HLM and mAb approach.
Conclusions All three methods investigated in this study appear suitable for use in the characterization of the CYP metabolism of new chemical entities produced during early drug discovery.</abstract><cop>Oxford, UK</cop><pub>Blackwell Science Ltd</pub><pmid>12580989</pmid><doi>10.1046/j.1365-2125.2003.01721.x</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Analytical, structural and metabolic biochemistry Antibodies, Monoclonal - pharmacology Biological and medical sciences Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 Enzyme System - analysis Cytochrome P-450 Enzyme System - metabolism Drug Design Drug Disposition Enzymes and enzyme inhibitors Fundamental and applied biological sciences. Psychology HLM monoclonal antibody Humans intrinsic clearance Oxidoreductases Phenotype reaction phenotyping recombinant CYP |
| title | A comparison of relative abundance, activity factor and inhibitory monoclonal antibody approaches in the characterization of human CYP enzymology |
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