Inhibition of cytochrome P450 enzymes by saturated and unsaturated fatty acids in human liver microsomes, characterization of enzyme kinetics in the presence of bovine serum albumin (0.1 and 1.0% w/v) and in vitro – in vivo extrapolation of hepatic clearance
The objective of the study was to determine the effect of fatty acids on CYP enzymes and the effect of BSA on intrinsic clearance of probe substrates. The inhibitory effect of thirteen fatty acids including saturated, mono-unsaturated and polyunsaturated fatty acids on CYP enzymes, kinetic parameter...
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Veröffentlicht in: | European journal of pharmaceutical sciences 2017-04, Vol.101, p.80-89 |
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creator | Palacharla, Raghava Choudary Uthukam, Venkatesham Manoharan, Arunkumar Ponnamaneni, Ranjith Kumar Padala, Nagasurya Prakash Boggavarapu, Rajesh Kumar Bhyrapuneni, Gopinadh Ajjala, Devender Reddy Nirogi, Ramakrishna |
description | The objective of the study was to determine the effect of fatty acids on CYP enzymes and the effect of BSA on intrinsic clearance of probe substrates. The inhibitory effect of thirteen fatty acids including saturated, mono-unsaturated and polyunsaturated fatty acids on CYP enzymes, kinetic parameters and intrinsic clearance values of nine CYP marker probe substrate reactions in the absence and presence of BSA (0.1 and 1.0% w/v) were characterized in human liver microsomes. The results demonstrate that most of the unsaturated fatty acids showed marked inhibition towards CYP2C8 mediated amodiaquine N-deethylation followed by inhibition of CYP2C9 and CYP2B6 mediated activities. The addition of 0.1% BSA in the incubation markedly improved the unbound intrinsic clearance values of probe substrates by reducing the Km values with little or no effect on maximal velocity. The addition of BSA (0.1 and 1.0% w/v) did not influence the unbound intrinsic clearance of marker reactions for CYP2A6, and CYP3A4 enzymes. The addition of 0.1% w/v BSA is sufficient to determine the intrinsic clearance of marker probe reactions by metabolite formation approach. The predicted hepatic clearance values for the substrates using the well-stirred model, in the presence of BSA (0.1% BSA), are comparable to the in vivo hepatic clearance values.
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doi_str_mv | 10.1016/j.ejps.2017.01.027 |
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[Display omitted]</description><identifier>ISSN: 0928-0987</identifier><identifier>EISSN: 1879-0720</identifier><identifier>DOI: 10.1016/j.ejps.2017.01.027</identifier><identifier>PMID: 28179134</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Bovine serum albumin (BSA) ; CYP450 enzymes ; Cytochrome P-450 Enzyme Inhibitors - pharmacology ; Cytochrome P-450 Enzyme System - metabolism ; Enzyme inhibition ; Fatty acids ; Fatty Acids - pharmacology ; Fatty Acids, Unsaturated - pharmacology ; Hepatic clearance ; Humans ; In vitro – In vivo extrapolation (IVIVE) ; Intrinsic clearance ; Kinetics ; Liver - drug effects ; Liver - metabolism ; Michaelis-Menten kinetics ; Microsomes, Liver - drug effects ; Microsomes, Liver - metabolism ; Serum Albumin, Bovine - metabolism ; Well-stirred model</subject><ispartof>European journal of pharmaceutical sciences, 2017-04, Vol.101, p.80-89</ispartof><rights>2017 Elsevier B.V.</rights><rights>Copyright © 2017 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c422t-f3ebeec890007212ec7b8afe0fb910309d3965270465d032159a343e2fb202d33</citedby><cites>FETCH-LOGICAL-c422t-f3ebeec890007212ec7b8afe0fb910309d3965270465d032159a343e2fb202d33</cites><orcidid>0000-0001-6741-8688</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejps.2017.01.027$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,781,785,3551,27928,27929,45999</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28179134$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Palacharla, Raghava Choudary</creatorcontrib><creatorcontrib>Uthukam, Venkatesham</creatorcontrib><creatorcontrib>Manoharan, Arunkumar</creatorcontrib><creatorcontrib>Ponnamaneni, Ranjith Kumar</creatorcontrib><creatorcontrib>Padala, Nagasurya Prakash</creatorcontrib><creatorcontrib>Boggavarapu, Rajesh Kumar</creatorcontrib><creatorcontrib>Bhyrapuneni, Gopinadh</creatorcontrib><creatorcontrib>Ajjala, Devender Reddy</creatorcontrib><creatorcontrib>Nirogi, Ramakrishna</creatorcontrib><title>Inhibition of cytochrome P450 enzymes by saturated and unsaturated fatty acids in human liver microsomes, characterization of enzyme kinetics in the presence of bovine serum albumin (0.1 and 1.0% w/v) and in vitro – in vivo extrapolation of hepatic clearance</title><title>European journal of pharmaceutical sciences</title><addtitle>Eur J Pharm Sci</addtitle><description>The objective of the study was to determine the effect of fatty acids on CYP enzymes and the effect of BSA on intrinsic clearance of probe substrates. The inhibitory effect of thirteen fatty acids including saturated, mono-unsaturated and polyunsaturated fatty acids on CYP enzymes, kinetic parameters and intrinsic clearance values of nine CYP marker probe substrate reactions in the absence and presence of BSA (0.1 and 1.0% w/v) were characterized in human liver microsomes. The results demonstrate that most of the unsaturated fatty acids showed marked inhibition towards CYP2C8 mediated amodiaquine N-deethylation followed by inhibition of CYP2C9 and CYP2B6 mediated activities. The addition of 0.1% BSA in the incubation markedly improved the unbound intrinsic clearance values of probe substrates by reducing the Km values with little or no effect on maximal velocity. The addition of BSA (0.1 and 1.0% w/v) did not influence the unbound intrinsic clearance of marker reactions for CYP2A6, and CYP3A4 enzymes. The addition of 0.1% w/v BSA is sufficient to determine the intrinsic clearance of marker probe reactions by metabolite formation approach. The predicted hepatic clearance values for the substrates using the well-stirred model, in the presence of BSA (0.1% BSA), are comparable to the in vivo hepatic clearance values.
[Display omitted]</description><subject>Bovine serum albumin (BSA)</subject><subject>CYP450 enzymes</subject><subject>Cytochrome P-450 Enzyme Inhibitors - pharmacology</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Enzyme inhibition</subject><subject>Fatty acids</subject><subject>Fatty Acids - pharmacology</subject><subject>Fatty Acids, Unsaturated - pharmacology</subject><subject>Hepatic clearance</subject><subject>Humans</subject><subject>In vitro – In vivo extrapolation (IVIVE)</subject><subject>Intrinsic clearance</subject><subject>Kinetics</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Michaelis-Menten kinetics</subject><subject>Microsomes, Liver - drug effects</subject><subject>Microsomes, Liver - metabolism</subject><subject>Serum Albumin, Bovine - metabolism</subject><subject>Well-stirred model</subject><issn>0928-0987</issn><issn>1879-0720</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9Uctu1TAQDaiIXgo_wALNBqlI3HTs3JuHxAZVPCpVggWsLceZKL4kcbCdQLriH_hDvgTnpi07VvZozpwzc04UPWcYM2TpxSGmw-BijiyLkcXIs4fRhuVZscWM40m0wYLnWyzy7DR64twBEdM8w8fRKc9ZVrBkt3lwctU3utRemx5MDWr2RjXWdASfd3sE6m_mjhyUMzjpRys9VSD7Csb-X11L72eQSlcOdA_N2MkeWj2RhU4ra1ygc69BNdJK5cnqG3mnt_LDN92T1-o47huCwZKjXtECKc0UuuDIjh3Ithy7ADoPFhz3CGe_hB8X06tjFTqT9tbAn1-_12IyQD-9lYNp70UbGsJfgWopbBRknkaPatk6enb7nkVf37_7cvlxe_3pw9Xl2-ut2nHut3VCJZHKi2BkxhknlZW5rAnrsmCYYFElRbrnGe7SfYUJZ_tCJruEeF1y5FWSnEXnK-9gzfeRnBeddoraVvZkRidYnqZpkbCcByhfoYt_zlItBqs7aWfBUCzpi4NY0hdL-gKZCOmHoRe3_GPZUXU_chd3ALxZARSunDRZ4ZRejK60JeVFZfT_-P8CLVLE8A</recordid><startdate>20170401</startdate><enddate>20170401</enddate><creator>Palacharla, Raghava Choudary</creator><creator>Uthukam, Venkatesham</creator><creator>Manoharan, Arunkumar</creator><creator>Ponnamaneni, Ranjith Kumar</creator><creator>Padala, Nagasurya Prakash</creator><creator>Boggavarapu, Rajesh Kumar</creator><creator>Bhyrapuneni, Gopinadh</creator><creator>Ajjala, Devender Reddy</creator><creator>Nirogi, Ramakrishna</creator><general>Elsevier B.V</general><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><orcidid>https://orcid.org/0000-0001-6741-8688</orcidid></search><sort><creationdate>20170401</creationdate><title>Inhibition of cytochrome P450 enzymes by saturated and unsaturated fatty acids in human liver microsomes, characterization of enzyme kinetics in the presence of bovine serum albumin (0.1 and 1.0% w/v) and in vitro – in vivo extrapolation of hepatic clearance</title><author>Palacharla, Raghava Choudary ; Uthukam, Venkatesham ; Manoharan, Arunkumar ; Ponnamaneni, Ranjith Kumar ; Padala, Nagasurya Prakash ; Boggavarapu, Rajesh Kumar ; Bhyrapuneni, Gopinadh ; Ajjala, Devender Reddy ; Nirogi, Ramakrishna</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c422t-f3ebeec890007212ec7b8afe0fb910309d3965270465d032159a343e2fb202d33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Bovine serum albumin (BSA)</topic><topic>CYP450 enzymes</topic><topic>Cytochrome P-450 Enzyme Inhibitors - pharmacology</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>Enzyme inhibition</topic><topic>Fatty acids</topic><topic>Fatty Acids - pharmacology</topic><topic>Fatty Acids, Unsaturated - pharmacology</topic><topic>Hepatic clearance</topic><topic>Humans</topic><topic>In vitro – In vivo extrapolation (IVIVE)</topic><topic>Intrinsic clearance</topic><topic>Kinetics</topic><topic>Liver - drug effects</topic><topic>Liver - metabolism</topic><topic>Michaelis-Menten kinetics</topic><topic>Microsomes, Liver - drug effects</topic><topic>Microsomes, Liver - metabolism</topic><topic>Serum Albumin, Bovine - metabolism</topic><topic>Well-stirred model</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Palacharla, Raghava Choudary</creatorcontrib><creatorcontrib>Uthukam, Venkatesham</creatorcontrib><creatorcontrib>Manoharan, Arunkumar</creatorcontrib><creatorcontrib>Ponnamaneni, Ranjith Kumar</creatorcontrib><creatorcontrib>Padala, Nagasurya Prakash</creatorcontrib><creatorcontrib>Boggavarapu, Rajesh Kumar</creatorcontrib><creatorcontrib>Bhyrapuneni, Gopinadh</creatorcontrib><creatorcontrib>Ajjala, Devender Reddy</creatorcontrib><creatorcontrib>Nirogi, Ramakrishna</creatorcontrib><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><jtitle>European journal of pharmaceutical sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Palacharla, Raghava Choudary</au><au>Uthukam, Venkatesham</au><au>Manoharan, Arunkumar</au><au>Ponnamaneni, Ranjith Kumar</au><au>Padala, Nagasurya Prakash</au><au>Boggavarapu, Rajesh Kumar</au><au>Bhyrapuneni, Gopinadh</au><au>Ajjala, Devender Reddy</au><au>Nirogi, Ramakrishna</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of cytochrome P450 enzymes by saturated and unsaturated fatty acids in human liver microsomes, characterization of enzyme kinetics in the presence of bovine serum albumin (0.1 and 1.0% w/v) and in vitro – in vivo extrapolation of hepatic clearance</atitle><jtitle>European journal of pharmaceutical sciences</jtitle><addtitle>Eur J Pharm Sci</addtitle><date>2017-04-01</date><risdate>2017</risdate><volume>101</volume><spage>80</spage><epage>89</epage><pages>80-89</pages><issn>0928-0987</issn><eissn>1879-0720</eissn><abstract>The objective of the study was to determine the effect of fatty acids on CYP enzymes and the effect of BSA on intrinsic clearance of probe substrates. The inhibitory effect of thirteen fatty acids including saturated, mono-unsaturated and polyunsaturated fatty acids on CYP enzymes, kinetic parameters and intrinsic clearance values of nine CYP marker probe substrate reactions in the absence and presence of BSA (0.1 and 1.0% w/v) were characterized in human liver microsomes. The results demonstrate that most of the unsaturated fatty acids showed marked inhibition towards CYP2C8 mediated amodiaquine N-deethylation followed by inhibition of CYP2C9 and CYP2B6 mediated activities. The addition of 0.1% BSA in the incubation markedly improved the unbound intrinsic clearance values of probe substrates by reducing the Km values with little or no effect on maximal velocity. The addition of BSA (0.1 and 1.0% w/v) did not influence the unbound intrinsic clearance of marker reactions for CYP2A6, and CYP3A4 enzymes. The addition of 0.1% w/v BSA is sufficient to determine the intrinsic clearance of marker probe reactions by metabolite formation approach. The predicted hepatic clearance values for the substrates using the well-stirred model, in the presence of BSA (0.1% BSA), are comparable to the in vivo hepatic clearance values.
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subjects | Bovine serum albumin (BSA) CYP450 enzymes Cytochrome P-450 Enzyme Inhibitors - pharmacology Cytochrome P-450 Enzyme System - metabolism Enzyme inhibition Fatty acids Fatty Acids - pharmacology Fatty Acids, Unsaturated - pharmacology Hepatic clearance Humans In vitro – In vivo extrapolation (IVIVE) Intrinsic clearance Kinetics Liver - drug effects Liver - metabolism Michaelis-Menten kinetics Microsomes, Liver - drug effects Microsomes, Liver - metabolism Serum Albumin, Bovine - metabolism Well-stirred model |
title | Inhibition of cytochrome P450 enzymes by saturated and unsaturated fatty acids in human liver microsomes, characterization of enzyme kinetics in the presence of bovine serum albumin (0.1 and 1.0% w/v) and in vitro – in vivo extrapolation of hepatic clearance |
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